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Himaja A, Routholla G, Patel T, Banerjee S, Begum D, Regula S, Pulya S, Biswas S, Adhikari N, Ghosh B. Design and synthesis of pyridine-based benzamides as potent HDAC3 inhibitors as an armament against breast cancer with in vivo validation. Eur J Med Chem 2025; 291:117636. [PMID: 40267875 DOI: 10.1016/j.ejmech.2025.117636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 04/10/2025] [Accepted: 04/12/2025] [Indexed: 04/25/2025]
Abstract
Some novel benzamide derivatives with modified linker group were designed and synthesized as promising HDAC3-selective inhibitors. These compounds exerted promising antiproliferative potential compared to reference molecule CI994 while tested against several cancer cell lines. Notably, all these molecules exhibited nontoxicity towards normal human cell lines. The most promising molecule in series 7c exhibited ∼47-fold HDAC3 selectivity over HDAC2 isoform. Compound 7c induced apoptosis and cell cycle arrest in the G2/M phase in the 4T1 cell line. Moreover, compound 7c yielded a good in vivo pharmacokinetic profile. Notably, compound 7c markedly reduced tumor growth in the 4T1-Luc breast cancer xenograft model in female Balb/c mice. Compound 7c also upregulated apoptotic proteins namely caspase-3, caspase-7, and cytochrome c, and downregulated Bcl-2. The antitumor potential of compound 7c was further justified by the downregulation of EGFR and Ki-67 through Western blot analysis. Nevertheless, the HDAC3 inhibitory potency of compound 7c depicted strong and stable binding interaction at the HDAC3 active site. These findings validated that compound 7c is a promising HDAC3 inhibitor that can be further investigated for clinical translation to achieve emerging breast cancer therapeutics.
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Affiliation(s)
- Ambati Himaja
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Shamirpet, Hyderabad, 500078, India
| | - Ganesh Routholla
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Shamirpet, Hyderabad, 500078, India
| | - Tarun Patel
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Shamirpet, Hyderabad, 500078, India
| | - Suvankar Banerjee
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P. O. Box 17020, Jadavpur University, Kolkata, 700032, West Bengal, India; School of Pharmacy, The Neotia University, Sarisa, Diamond Harbour Road, 24 Parganas (South), West Bengal, 743368, India
| | - Darakhshan Begum
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Shamirpet, Hyderabad, 500078, India
| | - Sanjeev Regula
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Shamirpet, Hyderabad, 500078, India
| | - Sravani Pulya
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Shamirpet, Hyderabad, 500078, India
| | - Swati Biswas
- Nanomedicine Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Shamirpet, Hyderabad, 500078, India
| | - Nilanjan Adhikari
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P. O. Box 17020, Jadavpur University, Kolkata, 700032, West Bengal, India.
| | - Balaram Ghosh
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Shamirpet, Hyderabad, 500078, India.
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Meng F, He J, Zhang X, Lyu W, Wei R, Wang S, Du Z, Wang H, Bi J, Hua X, Zhang C, Guan Y, Lyu G, Tian XL, Zhang L, Xie W, Tao W. Histone Lactylation Antagonizes Senescence and Skeletal Muscle Aging by Modulating Aging-Related Pathways. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2412747. [PMID: 40388671 DOI: 10.1002/advs.202412747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 04/11/2025] [Indexed: 05/21/2025]
Abstract
Epigenetic alterations are among the prominent drivers of cellular senescence and/or aging, intricately orchestrating gene expression programs during these processes. This study shows that histone lactylation, plays a pivotal role in counteracting senescence and mitigating dysfunctions of skeletal muscle in aged mice. Mechanistically, histone lactylation and lactyl-CoA levels markedly decrease during cellular senescence but are restored under hypoxic conditions primarily due to elevated glycolytic activity. The enrichment of histone lactylation at promoters is essential for sustaining the expression of genes involved in the cell cycle and DNA repair pathways. Furthermore, the modulation of enzymes crucial for histone lactylation, leads to reduced histone lactylation and accelerated cellular senescence. Consistently, the suppression of glycolysis and the depletion of histone lactylation are also observed during skeletal muscle aging. Modulating the enzymes can also lead to the loss of histone lactylation in skeletal muscle, downregulating DNA repair and proteostasis pathways and accelerating muscle aging. Running exercise increases histone lactylation, which in turn upregulate key genes in the DNA repair and proteostasis pathways. This study highlights the significant roles of histone lactylation in modulating cellular senescence as well as muscle aging, providing a promising avenue for antiaging intervention via metabolic manipulation.
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Affiliation(s)
- Fanju Meng
- The State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Jianuo He
- The State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Xuebin Zhang
- The State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Wencong Lyu
- The State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Ran Wei
- The State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Shiyi Wang
- The State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Zhehao Du
- The State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Haochen Wang
- The State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Jinlong Bi
- The State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Xueyang Hua
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - Chao Zhang
- Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
| | - Yiting Guan
- Zhanjiang Institute of Clinical Medicine, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, 524045, China
| | - Guoliang Lyu
- The State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Xiao-Li Tian
- Department of Human Population Genetics, Human Aging Research Institute (HARI) and School of Life Sciences, Nanchang University, Nanchang, 330031, China
| | - Lijun Zhang
- The State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Wenbing Xie
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - Wei Tao
- The State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China
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Tallan A, Kucinski J, Sunkel B, Taslim C, LaHaye S, Liu Q, Qi J, Wang M, Kendall GC, Stanton BZ. Highly quantitative measurement of differential protein-genome binding with PerCell chromatin sequencing. CELL REPORTS METHODS 2025:101052. [PMID: 40393455 DOI: 10.1016/j.crmeth.2025.101052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 03/21/2025] [Accepted: 04/24/2025] [Indexed: 05/22/2025]
Abstract
Quantitative comparison of ChIP-seq profiling between experimental conditions or samples remains technically challenging for the epigenetics field. Here, we report a strategy combining the use of well-defined cellular spike-in ratios of orthologous species' chromatin and a bioinformatic analysis pipeline to facilitate highly quantitative comparisons of 2D chromatin sequencing across experimental conditions. We find that the PerCell methodology results in efficient and consistent levels of spike-in vs. experimental genomic reads. We demonstrate use of the method and pipeline to enable quantitative, internally normalized chromatin sequencing on zebrafish embryos and human cancer cells. Overall, we propose the PerCell method to enable cross-species comparative epigenomics and promote uniformity of data analyses and sharing across labs.
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Affiliation(s)
- Alexi Tallan
- Nationwide Children's Hospital, Center for Childhood Cancer Research, Columbus, OH, USA; Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus, OH, USA
| | - Jack Kucinski
- Nationwide Children's Hospital, Center for Childhood Cancer Research, Columbus, OH, USA; Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus, OH, USA
| | - Benjamin Sunkel
- Nationwide Children's Hospital, Center for Childhood Cancer Research, Columbus, OH, USA
| | - Cenny Taslim
- Nationwide Children's Hospital, Center for Childhood Cancer Research, Columbus, OH, USA
| | - Stephanie LaHaye
- Nationwide Children's Hospital, Center for Childhood Cancer Research, Columbus, OH, USA
| | - Qi Liu
- Cancer Biology Department, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jun Qi
- Cancer Biology Department, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Meng Wang
- Nationwide Children's Hospital, Center for Childhood Cancer Research, Columbus, OH, USA.
| | - Genevieve C Kendall
- Nationwide Children's Hospital, Center for Childhood Cancer Research, Columbus, OH, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
| | - Benjamin Z Stanton
- Nationwide Children's Hospital, Center for Childhood Cancer Research, Columbus, OH, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA; Department of Biological Chemistry & Pharmacology, The Ohio State University College of Medicine, Columbus, OH, USA.
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Pires GS, Tolomeu HV, Rodrigues DA, Lima LM, Fraga CAM, Pinheiro PDSM. Drug Discovery for Histone Deacetylase Inhibition: Past, Present and Future of Zinc-Binding Groups. Pharmaceuticals (Basel) 2025; 18:577. [PMID: 40284012 PMCID: PMC12030391 DOI: 10.3390/ph18040577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 04/29/2025] Open
Abstract
Histone deacetylases (HDACs) are key regulators of gene expression, influencing chromatin remodeling and playing a crucial role in various physiological and pathological processes. Aberrant HDAC activity has been linked to cancer, neurodegenerative disorders, and inflammatory diseases, making these enzymes attractive therapeutic targets. HDAC inhibitors (HDACis) have gained significant attention, particularly those containing zinc-binding groups (ZBGs), which interact directly with the catalytic zinc ion in the enzyme's active site. The structural diversity of ZBGs profoundly impacts the potency, selectivity, and pharmacokinetics of HDACis. While hydroxamic acids remain the most widely used ZBGs, their limitations, such as metabolic instability and off-target effects, have driven the development of alternative scaffolds, including ortho-aminoanilides, mercaptoacetamides, alkylhydrazides, oxadiazoles, and more. This review explores the structural and mechanistic aspects of different ZBGs, their interactions with HDAC isoforms, and their influence on inhibitor selectivity. Advances in structure-based drug design have allowed the fine-tuning of HDACi pharmacophores, leading to more selective and efficacious compounds with improved drug-like properties. Understanding the nuances of ZBG interactions is essential for the rational design of next-generation HDACis, with potential applications in oncology, neuroprotection, and immunotherapy.
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Affiliation(s)
- Gustavo Salgado Pires
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil; (G.S.P.); (H.V.T.); (L.M.L.)
- Programa de Pós-Graduação em Farmacologia e Química Medicinal (PPGFQM), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil
| | - Heber Victor Tolomeu
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil; (G.S.P.); (H.V.T.); (L.M.L.)
| | - Daniel Alencar Rodrigues
- School of Pharmacy and Biomolecular Sciences (PBS), Royal College of Surgeons in Ireland, 1st Floor Ardilaun House Block B, 111 St Stephen’s Green, Dublin 2, Ireland;
| | - Lídia Moreira Lima
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil; (G.S.P.); (H.V.T.); (L.M.L.)
- Programa de Pós-Graduação em Farmacologia e Química Medicinal (PPGFQM), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil
- Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil
| | - Carlos Alberto Manssour Fraga
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil; (G.S.P.); (H.V.T.); (L.M.L.)
- Programa de Pós-Graduação em Farmacologia e Química Medicinal (PPGFQM), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil
- Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil
| | - Pedro de Sena Murteira Pinheiro
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil; (G.S.P.); (H.V.T.); (L.M.L.)
- Programa de Pós-Graduação em Farmacologia e Química Medicinal (PPGFQM), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil
- Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil
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Hao W, Zhang Q, Ma Y, Ding Y, Zhao C, Tian C. Mechanism and application of HDAC inhibitors in the treatment of hepatocellular carcinoma. J Mol Med (Berl) 2025; 103:469-484. [PMID: 40131444 DOI: 10.1007/s00109-025-02532-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 01/02/2025] [Accepted: 03/14/2025] [Indexed: 03/27/2025]
Abstract
Hepatoma is the sixth most malignant tumor in the world and the second leading cause of cancer death. Among the types of hepatoma, hepatocellular carcinoma (HCC) is the most important pathological type. For patients with early-stage HCC, the curative treatment is tumor resection. However, early diagnosis and treatment of HCC are difficult; the disease progresses rapidly, and the prognosis is poor. Due to the current limited treatment options for advanced HCC, the identification of new targeted agents is critical for the development of novel approaches to HCC treatment. Histone deacetylases (HDACs) is a protease that removes acetyl groups from histone lysine residues in proteins, and it plays an important role in the structural modification of chromosomes and the regulation of gene expression. Abnormally expressed HDACs can promote tumorigenesis by inducing biological processes such as cell proliferation, migration, and apoptosis inhibition. Since HDACs activity is upregulated in HCC, treatment regimens specifically inhibiting various HDACs have shown good efficacy. This article reviews the application of HDAC inhibitors in the treatment of HCC and explains their mechanisms of action. KEY MESSAGES: HDAC network and cellular effects of HDAC inhibitors. Role and mechanism of HDAC inhibitors in HCC. HDAC inhibitor combined with other ways to treat HCC. The side effects of HDACis in the treatment of HCC.
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Affiliation(s)
- Wei Hao
- School of Life Science and Technology, Shandong Second Medical University, Weifang, 261053, Shandong Province, China
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, 102206, China
- Laboratory of Immune Microenvironment and Inflammatory Disease Research in Universities of Shandong Province, Shandong Second Medical University, Weifang, 261053, Shandong Province, China
| | - Qingchen Zhang
- School of Life Science and Technology, Shandong Second Medical University, Weifang, 261053, Shandong Province, China
- Laboratory of Immune Microenvironment and Inflammatory Disease Research in Universities of Shandong Province, Shandong Second Medical University, Weifang, 261053, Shandong Province, China
| | - Yuan Ma
- School of Life Science and Technology, Shandong Second Medical University, Weifang, 261053, Shandong Province, China
- Laboratory of Immune Microenvironment and Inflammatory Disease Research in Universities of Shandong Province, Shandong Second Medical University, Weifang, 261053, Shandong Province, China
| | - Yue Ding
- School of Life Science and Technology, Shandong Second Medical University, Weifang, 261053, Shandong Province, China
- Laboratory of Immune Microenvironment and Inflammatory Disease Research in Universities of Shandong Province, Shandong Second Medical University, Weifang, 261053, Shandong Province, China
| | - Chunling Zhao
- School of Life Science and Technology, Shandong Second Medical University, Weifang, 261053, Shandong Province, China.
- Laboratory of Immune Microenvironment and Inflammatory Disease Research in Universities of Shandong Province, Shandong Second Medical University, Weifang, 261053, Shandong Province, China.
| | - Chunyan Tian
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, 102206, China.
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Bashir K, Todaka D, Sako K, Ueda M, Aziz F, Seki M. Chemical application improves stress resilience in plants. PLANT MOLECULAR BIOLOGY 2025; 115:47. [PMID: 40105987 PMCID: PMC11922999 DOI: 10.1007/s11103-025-01566-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 02/12/2025] [Indexed: 03/22/2025]
Abstract
In recent years, abiotic stresses, including droughts, floods, high temperatures, and salinity, have become increasingly frequent and severe. These stresses significantly hinder crop yields and product quality, posing substantial challenges to sustainable agriculture and global food security. Simultaneously, the rapidly growing global population exacerbates the need to enhance crop production under worsening environmental conditions. Consequently, the development of effective strategies to strengthen the resilience of crop plants against high temperatures, water scarcity, and extreme environmental conditions is critical for mitigating the impacts of abiotic stress. Plants respond to these environmental challenges by reprogramming their transcriptome and metabolome. Common strategies for developing stress-tolerant plants include screening germplasm, generating transgenic crop plants, and employing genome editing techniques. Recently, chemical treatment has emerged as a promising approach to enhance abiotic stress tolerance in crops. This technique involves the application of exogenous chemical compounds that induce molecular and physiological changes, thereby providing a protective shield against abiotic stress. Forward and reverse genetic approaches have facilitated the identification of chemicals capable of modulating plant responses to abiotic stresses. These priming agents function as epigenetic regulators, agonists, or antagonists, playing essential roles in regulating stomatal closure to conserve water, managing cellular signaling through reactive oxygen species and metabolites to sustain plant growth, and activating gluconeogenesis to enhance cellular metabolism. This review summarizes recent advancements in the field of chemical priming and explores strategies to improve stress tolerance and crop productivity, thereby contributing to the enhancement of global food security.
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Grants
- 18H04791 Ministry of Education, Culture, Sports, Science and Technology
- 18H04705 Ministry of Education, Culture, Sports, Science and Technology
- 23119522 Ministry of Education, Culture, Sports, Science and Technology
- 25119724 Ministry of Education, Culture, Sports, Science and Technology
- CREST (JPMJCR13B4) the Japan Science and Technology Agency (JST)
- A-STEP (JPMJTM19BS) the Japan Science and Technology Agency (JST)
- GteX (JPMJGX23B0) the Japan Science and Technology Agency (JST)
- ASPIRE (JPMJAP24A3) Japan Society for Technology of Plasticity
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Affiliation(s)
- Khurram Bashir
- Plant Genomic Network Research Team, RIKEN Center for Sustainable Resource Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
- Department of Life Sciences, SBA School of Science and Engineering, , Lahore University of Management Sciences, DHA Phase 5, Lahore, Pakistan.
| | - Daisuke Todaka
- Plant Genomic Network Research Team, RIKEN Center for Sustainable Resource Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan
| | - Kaori Sako
- Plant Genomic Network Research Team, RIKEN Center for Sustainable Resource Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan
- Department of Advanced Bioscience, Faculty of Agriculture, Kindai University, Nakamachi, Nara, 3327-204, Japan
| | - Minoru Ueda
- Plant Genomic Network Research Team, RIKEN Center for Sustainable Resource Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan
- Plant Epigenome Regulation Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako, Saitama, Japan
| | - Farhan Aziz
- Plant Genomic Network Research Team, RIKEN Center for Sustainable Resource Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan
- Department of Life Sciences, SBA School of Science and Engineering, , Lahore University of Management Sciences, DHA Phase 5, Lahore, Pakistan
| | - Motoaki Seki
- Plant Genomic Network Research Team, RIKEN Center for Sustainable Resource Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
- Plant Epigenome Regulation Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako, Saitama, Japan.
- Kihara Institute for Biological Research, Yokohama City University, Yokohama, Japan.
- Graduate School of Science and Engineering, Saitama University, Saitama, Saitama, Japan.
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7
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Li J, Pan J, Wang L, Ji G, Dang Y. Colorectal Cancer: Pathogenesis and Targeted Therapy. MedComm (Beijing) 2025; 6:e70127. [PMID: 40060193 PMCID: PMC11885891 DOI: 10.1002/mco2.70127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 04/29/2025] Open
Abstract
Colorectal cancer (CRC) ranks among the most prevalent malignant neoplasms globally. A growing body of evidence underscores the pivotal roles of genetic alterations and dysregulated epigenetic modifications in the pathogenesis of CRC. In recent years, the reprogramming of tumor cell metabolism has been increasingly acknowledged as a hallmark of cancer. Substantial evidence suggests a crosstalk between tumor cell metabolic reprogramming and epigenetic modifications, highlighting a complex interplay between metabolism and the epigenetic genome that warrants further investigation. Biomarkers associated with the pathogenesis and metabolic characteristics of CRC hold significant clinical implications. Nevertheless, elucidating the genetic, epigenetic, and metabolic landscapes of CRC continues to pose considerable challenges. Here, we attempt to summarize the key genes driving the onset and progression of CRC and the related epigenetic regulators, clarify the roles of gene expression and signaling pathways in tumor metabolism regulation, and explore the potential crosstalk between epigenetic events and tumor metabolic reprogramming, providing a comprehensive mechanistic explanation for the malignant progression of CRC. Finally, by integrating reliable targets from genetics, epigenetics, and metabolic processes that hold promise for translation into clinical practice, we aim to offer more strategies to overcome the bottlenecks in CRC treatment.
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Affiliation(s)
- Jingyuan Li
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Jiashu Pan
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Lisheng Wang
- Department of BiochemistryMicrobiology and ImmunologyFaculty of MedicineUniversity of OttawaOttawaOntarioCanada
- China‐Canada Centre of Research for Digestive DiseasesUniversity of OttawaOttawaOntarioCanada
| | - Guang Ji
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Yanqi Dang
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
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Likasitwatanakul P, Li Z, Doan P, Spisak S, Raghawan AK, Liu Q, Liow P, Lee S, Chen D, Bala P, Sahgal P, Aitymbayev D, Thalappillil JS, Papanastasiou M, Hawkins W, Carr SA, Park H, Cleary JM, Qi J, Sethi NS. Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.06.626451. [PMID: 39713466 PMCID: PMC11661112 DOI: 10.1101/2024.12.06.626451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
Dysregulated epigenetic programs that restrict differentiation, reactivate fetal genes, and confer phenotypic plasticity are critical to colorectal cancer (CRC) development. By screening a small molecule library targeting epigenetic regulators using our dual reporter system, we found that inhibiting histone deacetylase (HDAC) 1/2 promotes CRC differentiation and anti-tumor activity. Comprehensive biochemical, chemical, and genetic experiments revealed that on-target blockade of the HDAC1/2 catalytic domain mediated the differentiated phenotype. Unbiased profiling of histone posttranslational modifications induced by HDAC1/2 inhibition nominated acetylation of specific histone lysine residues as potential regulators of differentiation. Genome-wide assessment of implicated marks indicated that H3K27ac gains at HDAC1/2-bound regions associated with open chromatin and upregulation of differentiation genes upon HDAC1/2 inhibition. Disrupting H3K27ac by degrading acetyltransferase EP300 rescued HDAC1/2 inhibitor-mediated differentiation of a patient-derived CRC model using single cell RNA-sequencing. Genetic screens revealed that DAPK3 contributes to CRC differentiation induced by HDAC1/2 inhibition. These results highlight the importance of specific chemically targetable histone modifications in governing cancer cell states and epigenetic reprogramming as a therapeutic strategy in CRC.
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Affiliation(s)
- Pornlada Likasitwatanakul
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Bangkok, Thailand
| | - Zhixin Li
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Paul Doan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Sandor Spisak
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Akhouri Kishore Raghawan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Qi Liu
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Priscilla Liow
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Sunwoo Lee
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - David Chen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Pratyusha Bala
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Pranshu Sahgal
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Daulet Aitymbayev
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Jennifer S. Thalappillil
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Malvina Papanastasiou
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - William Hawkins
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Steven A. Carr
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Haeseong Park
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA
| | - James M. Cleary
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jun Qi
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Nilay S. Sethi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA
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9
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Iriondo O, Mecenas D, Li Y, Chin CR, Thomas A, Moriarty A, Marker R, Wang YJ, Hendrick H, Amzaleg Y, Ortiz V, MacKay M, Dickerson A, Lee G, Harotoonian S, Benayoun BA, Smith A, Mason CE, Torres ETR, Klotz R, Yu M. Hypoxic Memory Mediates Prolonged Tumor-Intrinsic Type I Interferon Suppression to Promote Breast Cancer Progression. Cancer Res 2024; 84:3141-3157. [PMID: 38990731 PMCID: PMC11444891 DOI: 10.1158/0008-5472.can-23-2028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 05/03/2024] [Accepted: 07/03/2024] [Indexed: 07/13/2024]
Abstract
Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIF). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell lines and common breast cancer cell lines, hypoxia downregulated tumor-intrinsic type I IFN signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a "hypoxic memory" phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for circulating tumor cells during the metastatic cascade. Significance: Long-term cellular memory of hypoxia leads to sustained suppression of tumor-intrinsic type I IFN signaling and the antigen presentation pathway that facilitates tumorigenesis and metastasis. See related commentary by Purdy and Ford, p. 3125.
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Affiliation(s)
- Oihana Iriondo
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- Center for Cooperative Research (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio 48160, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Desirea Mecenas
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
| | - Yilin Li
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Christopher R. Chin
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA
| | - Amal Thomas
- Department of Molecular and Computational Biology, USC Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Aidan Moriarty
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Rebecca Marker
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Yiru Jess Wang
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Haley Hendrick
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Yonatan Amzaleg
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- Center for Craniofacial Molecular Biology, Ostrow School of Dentistry of the University of Southern California, Los Angeles, CA 90033, USA
| | - Veronica Ortiz
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
| | - Matthew MacKay
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
| | - Amber Dickerson
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
| | - Grace Lee
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
| | - Sevana Harotoonian
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
| | - Bérénice A. Benayoun
- USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
| | - Andrew Smith
- Department of Molecular and Computational Biology, USC Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Christopher E. Mason
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA
| | - Evanthia T. Roussos Torres
- USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
| | - Remi Klotz
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Min Yu
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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10
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Qin Y, Li Z, Zhang X, Li J, Teng Y, Zhang N, Zhao S, Kong L, Niu W. Pan-cancer exploration of PNO1: A prospective prognostic biomarker with ties to immune infiltration. Heliyon 2024; 10:e36819. [PMID: 39263087 PMCID: PMC11387552 DOI: 10.1016/j.heliyon.2024.e36819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 08/21/2024] [Accepted: 08/22/2024] [Indexed: 09/13/2024] Open
Abstract
The partner of NOB1 homolog (PNO1) is an RNA-binding protein that participates in ribosome biogenesis and protein modification. The functions of this molecule are largely unknown in cancers, particularly breast cancer. We employed bioinformatics methods to probe the putative oncogenic functions of PNO1 based on expression profiles and clinical data from the cancer genome atlas (TCGA), genotype-tissue expression project (GTEx), human protein atlas (HPA), cancer cell line encyclopedia (CCLE), UALCAN, drug sensitivity in cancer (GDSC) and UCSC XENA databases. Our analyses revealed that PNO1 was overexpressed in 31 malignancies, which excluded kidney chromophobe (KICH) and acute myeloid leukemia (LAML). Prognostic assessments have demonstrated that high PNO1 expression was significantly correlated with poor overall and disease-specific survival in various cancers. The promoter methylation level of PNO1 is significantly decreased in breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSC), kidney renal papillary cell carcinoma (KIRP), prostate adenocarcinoma (PRAD), thyroid carcinoma (THCA) and uterine corpus endometrial carcinoma (UCEC). Furthermore, inhibition of PNO1 decreased the viability, migration and invasion of breast cancer cells, and these results were confirmed by mouse xenograft models of breast cancer. In addition, we discovered that tumor microenvironment (TME), immune infiltration, and chemotherapy sensitivity were influenced by PNO1 expression. Concordantly, our analyses revealed a significant positive correlation between PNO1 and programmed cell death ligand 1 (PD-L1) expression across breast carcinoma samples. In conclusion, these findings indicate that PNO1 could act as a promising prognostic biomarker and adjunct diagnostic indicator, because it affects tumor growth and invasion. Our study offers valuable new perspectives on the oncogenic role of PNO1 in various types of cancers.
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Affiliation(s)
- Yinhui Qin
- Department of Pharmacy, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Zhen Li
- Department of Pathology, Henan Key Laboratory for Digital Pathology Medicine, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Xianwei Zhang
- Department of Pathology, Henan Key Laboratory for Digital Pathology Medicine, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Junjun Li
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, No. N1 Shangcheng Avenue, Hangzhou, 310058, Zhejiang, China
| | - Yuetai Teng
- Department of Pharmacy, Jinan Vocational College of Nursing, Jinan, 250102, China
| | - Na Zhang
- Shandong Academy of Chinese Medicine, Jinan, 250014, China
| | - Shengyu Zhao
- Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Lingfei Kong
- Department of Pathology, Henan Key Laboratory for Digital Pathology Medicine, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Weihong Niu
- Department of Pathology, Henan Key Laboratory for Digital Pathology Medicine, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China
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11
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Jamison JK, Zhou M, Gelmann EP, Luk L, Bates SE, Califano A, Fojo T. Entinostat in patients with relapsed or refractory abdominal neuroendocrine tumors. Oncologist 2024; 29:817-e1213. [PMID: 38886159 PMCID: PMC11379646 DOI: 10.1093/oncolo/oyae118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 04/19/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms with an increasing annual incidence and prevalence. Many are metastatic at presentation or recur following surgical resection and require systemic therapy, for which somatostatin analogs such as octreotide or lanreotide comprise typical first-line therapies. Nonetheless, treatment options remain limited. Epigenetic processes such as histone modifications have been implicated in malignant transformation and progression. In this study, we evaluated the anti-proliferative effects of a histone deacetylase (HDAC) inhibitor, entinostat, which was computationally predicted to show anti-cancer activity, as confirmed in in vitro and in vivo models of GEP-NETs. METHODS This was a phase II study to evaluate the efficacy and safety of entinostat in patients with relapsed or refractory abdominal NETs. The primary objective was to estimate the objective response rate to entinostat. Additionally, with each patient as his/her own control we estimated the rates of tumor growth prior to enrollment on study and while receiving entinostat. Patients received 5 mg entinostat weekly until disease progression or intolerable toxicity. The dose could be changed to 10 mg biweekly for patients who did not experience grade ≥ 2 treatment-related adverse events (AEs) in cycle 1, but was primarily administered at the starting 5 mg weekly dose. RESULTS The study enrolled only 5 patients due to early termination by the drug sponsor. The first patient that enrolled had advanced disease and died within days of enrollment before follow-up imaging due to a grade 5 AE unrelated to study treatment and was considered non-evaluable. Best RECIST response for the remaining 4 patients was stable disease (SD) with time on study of 154+, 243, 574, and 741 days. With each patient as his/her own control, rates of tumor growth on entinostat were markedly reduced with rates 17%, 20%, 33%, and 68% of the rates prior to enrollment on study. Toxicities possibly or definitely related to entinostat included grade 2/3 neutrophil count decrease [2/4 (50%)/ 2/4 (50%)], grade 3 hypophosphatemia [1/4, (25%)], grade 1/2 fatigue [1/4 (25%)/ 2/4 (50%)], and other self-limiting grade 1/2 AEs. CONCLUSION In the treatment of relapsed or refractory abdominal NETs, entinostat 5 mg weekly led to prolonged SD and reduced the rate of tumor growth by 32% to 83% with an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03211988).
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Affiliation(s)
| | - Mengxi Zhou
- Department of Medicine, Division of Hematology Oncology, Columbia
University Irving Medical Center, New York, NY,
United States
| | | | - Lyndon Luk
- Department of Radiology, Columbia University Irving Medical
Center, New York, NY, United States
| | - Susan E Bates
- Department of Medicine, Division of Hematology Oncology, Columbia
University Irving Medical Center, New York, NY,
United States
| | - Andrea Califano
- Department of Medicine, Division of Hematology Oncology, Columbia
University Irving Medical Center, New York, NY,
United States
- Department of Systems Biology, Columbia University Irving Medical
Center, New York, NY, United States
- Department of Biochemistry and Molecular Biophysics, Columbia University
Irving Medical Center, New York, NY, United States
- Chan Zuckerberg Biohub New York, New York,
NY, United States
- Department of Biomedical Informatics, Columbia University Irving Medical
Center, New York, United
States
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving
Medical Center, New York, United States
| | - Tito Fojo
- Department of Medicine, Division of Hematology Oncology, Columbia
University Irving Medical Center, New York, NY,
United States
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12
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Tallan A, Kucinski J, Sunkel B, Taslim C, LaHaye S, Liu Q, Qi J, Wang M, Kendall GC, Stanton BZ. Highly quantitative measurement of differential protein-genome binding with PerCell chromatin sequencing. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.12.603283. [PMID: 39071412 PMCID: PMC11275836 DOI: 10.1101/2024.07.12.603283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
We report a universal strategy for 2D chromatin sequencing, to increase uniform data analyses and sharing across labs, and to facilitate highly quantitative comparisons across experimental conditions. Within our system, we provide wetlab and drylab tools for researchers to establish and analyze protein-genome binding data with PerCell ChIP-seq. Our methodology is virtually no cost and flexible, enabling rapid, quantitative, internally normalized chromatin sequencing to catalyze project development in a variety of systems, including in vivo zebrafish epigenomics and cancer cell epigenomics. While we highlight utility in these key areas, our methodology is flexible enough such that rapid comparisons of cellular spike-in versus non spike-in are possible, and generalizability to nuclease-based 2D chromatin sequencing would also be possible within the framework of our pipeline. Through the use of well-defined cellular ratios containing orthologous species' chromatin, we enable cross-species comparative epigenomics and highly quantitative low-cost chromatin sequencing with utility across a range of disciplines.
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13
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Zhou C, Zhao D, Wu C, Wu Z, Zhang W, Chen S, Zhao X, Wu S. Role of histone deacetylase inhibitors in non-neoplastic diseases. Heliyon 2024; 10:e33997. [PMID: 39071622 PMCID: PMC11283006 DOI: 10.1016/j.heliyon.2024.e33997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 06/28/2024] [Accepted: 07/02/2024] [Indexed: 07/30/2024] Open
Abstract
Background Epigenetic dysregulation has been implicated in the development and progression of a variety of human diseases, but epigenetic changes are reversible, and epigenetic enzymes and regulatory proteins can be targeted using small molecules. Histone deacetylase inhibitors (HDACis), as a class of epigenetic drugs, are widely used to treat various cancers and other diseases involving abnormal gene expression. Results Specially, HDACis have emerged as a promising strategy to enhance the therapeutic effect of non-neoplastic conditions, including neurological disorders, cardiovascular diseases, renal diseases, autoimmune diseases, inflammatory diseases, infectious diseases and rare diseases, along with their related mechanisms. However, their clinical efficacy has been limited by drug resistance and toxicity. Conclusions To date, most clinical trials of HDAC inhibitors have been related to the treatment of cancer rather than the treatment of non-cancer diseases, for which experimental studies are gradually underway. Discussions regarding non-neoplastic diseases often concentrate on specific disease types. Therefore, this review highlights the development of HDACis and their potential therapeutic applications in non-neoplastic diseases, either as monotherapy or in combination with other drugs or therapies.
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Affiliation(s)
- Chunxiao Zhou
- College of Medicine, Qingdao University, Qingdao, 266000, China
| | - Dengke Zhao
- Harbin Medical University, Harbin, 150000, China
| | - Chunyan Wu
- College of Medicine, Qingdao University, Qingdao, 266000, China
| | - Zhimin Wu
- College of Medicine, Qingdao University, Qingdao, 266000, China
| | - Wen Zhang
- College of Medicine, Qingdao University, Qingdao, 266000, China
| | - Shilv Chen
- College of Medicine, Qingdao University, Qingdao, 266000, China
| | - Xindong Zhao
- College of Medicine, Qingdao University, Qingdao, 266000, China
| | - Shaoling Wu
- Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
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14
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Trionfetti F, Montaldo C, Caiello I, Bontempi G, Terri M, Tiberi M, Marchant V, Domenici A, Menè P, Cordani M, Zwergel C, Prencipe G, Ruiz-Ortega M, Valente S, Mai A, Tripodi M, Strippoli R. Mechanisms of mesothelial cell response to viral infections: HDAC1-3 inhibition blocks poly(I:C)-induced type I interferon response and modulates the mesenchymal/inflammatory phenotype. Front Cell Infect Microbiol 2024; 14:1308362. [PMID: 38476167 PMCID: PMC10927979 DOI: 10.3389/fcimb.2024.1308362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 01/24/2024] [Indexed: 03/14/2024] Open
Abstract
Infectious peritonitis is a leading cause of peritoneal functional impairment and a primary factor for therapy discontinuation in peritoneal dialysis (PD) patients. Although bacterial infections are a common cause of peritonitis episodes, emerging evidence suggests a role for viral pathogens. Toll-like receptors (TLRs) specifically recognize conserved pathogen-associated molecular patterns (PAMPs) from bacteria, viruses, and fungi, thereby orchestrating the ensuing inflammatory/immune responses. Among TLRs, TLR3 recognizes viral dsRNA and triggers antiviral response cascades upon activation. Epigenetic regulation, mediated by histone deacetylase (HDAC), has been demonstrated to control several cellular functions in response to various extracellular stimuli. Employing epigenetic target modulators, such as epidrugs, is a current therapeutic option in several cancers and holds promise in treating viral diseases. This study aims to elucidate the impact of TLR3 stimulation on the plasticity of human mesothelial cells (MCs) in PD patients and to investigate the effects of HDAC1-3 inhibition. Treatment of MCs from PD patients with the TLR3 agonist polyinosinic:polycytidylic acid (Poly(I:C)), led to the acquisition of a bona fide mesothelial-to-mesenchymal transition (MMT) characterized by the upregulation of mesenchymal genes and loss of epithelial-like features. Moreover, Poly(I:C) modulated the expression of several inflammatory cytokines and chemokines. A quantitative proteomic analysis of MCs treated with MS-275, an HDAC1-3 inhibitor, unveiled altered expression of several proteins, including inflammatory cytokines/chemokines and interferon-stimulated genes (ISGs). Treatment with MS-275 facilitated MMT reversal and inhibited the interferon signature, which was associated with reduced STAT1 phosphorylation. However, the modulation of inflammatory cytokine/chemokine production was not univocal, as IL-6 and CXCL8 were augmented while TNF-α and CXCL10 were decreased. Collectively, our findings underline the significance of viral infections in acquiring a mesenchymal-like phenotype by MCs and the potential consequences of virus-associated peritonitis episodes for PD patients. The observed promotion of MMT reversal and interferon response inhibition by an HDAC1-3 inhibitor, albeit without a general impact on inflammatory cytokine production, has translational implications deserving further analysis.
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Affiliation(s)
- Flavia Trionfetti
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
- Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Claudia Montaldo
- Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Ivan Caiello
- Division of Rheumatology, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy
| | - Giulio Bontempi
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
- Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Michela Terri
- Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Marta Tiberi
- Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Vanessa Marchant
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, Madrid, Spain
- 15 REDINREN/RICORS2040, Madrid, Spain
| | - Alessandro Domenici
- Renal Unit, Department of Clinical and Molecular Medicine, Sant’Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Paolo Menè
- Renal Unit, Department of Clinical and Molecular Medicine, Sant’Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University of Madrid, Madrid, Spain
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain
| | - Clemens Zwergel
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy
| | - Giusi Prencipe
- Division of Rheumatology, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy
| | - Marta Ruiz-Ortega
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, Madrid, Spain
- 15 REDINREN/RICORS2040, Madrid, Spain
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy
| | - Marco Tripodi
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
- Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Raffaele Strippoli
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
- Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy
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15
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Terri M, Sandoval P, Bontempi G, Montaldo C, Tomero-Sanz H, de Turris V, Trionfetti F, Pascual-Antón L, Clares-Pedrero I, Battistelli C, Valente S, Zwergel C, Mai A, Rosanò L, Del Pozo MÁ, Sánchez-Álvarez M, Cabañas C, Tripodi M, López-Cabrera M, Strippoli R. HDAC1/2 control mesothelium/ovarian cancer adhesive interactions impacting on Talin-1-α5β1-integrin-mediated actin cytoskeleton and extracellular matrix protein remodeling. J Exp Clin Cancer Res 2024; 43:27. [PMID: 38254102 PMCID: PMC10804625 DOI: 10.1186/s13046-023-02930-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 12/10/2023] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Peritoneal metastasis, which accounts for 85% of all epithelial ovarian carcinoma (EOC) metastases, is a multistep process that requires the establishment of adhesive interactions between cancer cells and the peritoneal membrane. Interrelations between EOC and the mesothelial stroma are critical to facilitate the metastatic process. No data is available so far on the impact of histone acetylation/deacetylation, a potentially relevant mechanism governing EOC metastasis, on mesothelial cells (MCs)-mediated adhesion. METHODS Static adhesion and peritoneal clearance experiments were performed pretreating mesenchymal-like MCs and platinum-sensitive/resistant EOC cell lines with MS-275-a Histone deacetylase (HDAC)1-3 pharmacological inhibitor currently used in combination trials. Results were acquired by confocal microscopy and were analyzed with an automated Opera software. The role of HDAC1/2 was validated by genetic silencing. The role of α4-, α5-α1 Integrins and Fibronectin-1 was validated using specific monoclonal antibodies. Quantitative proteomic analysis was performed on primary MCs pretreated with MS-275. Decellularized matrices were generated from either MS-275-exposed or untreated cells to study Fibronectin-1 extracellular secretion. The effect of MS-275 on β1 integrin activity was assessed using specific monoclonal antibodies. The role of Talin-1 in MCs/EOC adhesion was analyzed by genetic silencing. Talin-1 ectopic expression was validated as a rescue tool from MS-275-induced phenotype. The in vivo effect of MS-275-induced MC remodeling was validated in a mouse model of peritoneal EOC dissemination. RESULTS Treatment of MCs with non-cytotoxic concentrations of MS-275 caused a consistent reduction of EOC adhesion. Proteomic analysis revealed several pathways altered upon MC treatment with MS-275, including ECM deposition/remodeling, adhesion receptors and actin cytoskeleton regulators. HDAC1/2 inhibition hampered actin cytoskeleton polymerization by downregulating actin regulators including Talin-1, impairing β1 integrin activation, and leading to abnormal extracellular secretion and distribution of Fibronectin-1. Talin-1 ectopic expression rescued EOC adhesion to MS-275-treated MCs. In an experimental mouse model of metastatic EOC, MS-275 limited tumor invasion, Fibronectin-1 secretion and the sub-mesothelial accumulation of MC-derived carcinoma-associated fibroblasts. CONCLUSION Our study unveils a direct impact of HDAC-1/2 in the regulation of MC/EOC adhesion and highlights the regulation of MC plasticity by epigenetic inhibition as a potential target for therapeutic intervention in EOC peritoneal metastasis.
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Affiliation(s)
- Michela Terri
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
- National Institute for Infectious Diseases L. Spallanzani, IRCCS, Via Portuense, 292, 00149, Rome, Italy
| | - Pilar Sandoval
- Tissue and Organ Homeostasis Program, Cell-Cell Communication and Inflammation Unit, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Consejo Superior de Investigaciones Científicas, 28049, Madrid, Spain
| | - Giulio Bontempi
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
- National Institute for Infectious Diseases L. Spallanzani, IRCCS, Via Portuense, 292, 00149, Rome, Italy
| | - Claudia Montaldo
- National Institute for Infectious Diseases L. Spallanzani, IRCCS, Via Portuense, 292, 00149, Rome, Italy
| | - Henar Tomero-Sanz
- Tissue and Organ Homeostasis Program, Cell-Cell Communication and Inflammation Unit, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Consejo Superior de Investigaciones Científicas, 28049, Madrid, Spain
| | - Valeria de Turris
- Center for Life Nano- & Neuro-Science, Istituto Italiano di Tecnologia (IIT), 00161, Rome, Italy
| | - Flavia Trionfetti
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
- National Institute for Infectious Diseases L. Spallanzani, IRCCS, Via Portuense, 292, 00149, Rome, Italy
| | - Lucía Pascual-Antón
- Tissue and Organ Homeostasis Program, Cell-Cell Communication and Inflammation Unit, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Consejo Superior de Investigaciones Científicas, 28049, Madrid, Spain
| | - Irene Clares-Pedrero
- Tissue and Organ Homeostasis Program, Cell-Cell Communication and Inflammation Unit, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Consejo Superior de Investigaciones Científicas, 28049, Madrid, Spain
- Department of Immunology, Ophthalmology and Otorhinolaryngology, School of Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - Cecilia Battistelli
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Clemens Zwergel
- Department of Drug Chemistry and Technologies, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Laura Rosanò
- Institute of Molecular Biology and Pathology, CNR, Rome, Italy
| | - Miguel Ángel Del Pozo
- Mechanoadaptation and Caveolae Biology Lab, Area of Cell and Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Miguel Sánchez-Álvarez
- Cell Compartmentalization, Homeostasis and Inflammation lab. Department of Metabolic and Immunity Diseases, Instituto de Investigaciones Biomédicas "Sols-Morreale", 28029, Madrid, Spain
| | - Carlos Cabañas
- Tissue and Organ Homeostasis Program, Cell-Cell Communication and Inflammation Unit, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Consejo Superior de Investigaciones Científicas, 28049, Madrid, Spain
- Department of Immunology, Ophthalmology and Otorhinolaryngology, School of Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain
| | - Marco Tripodi
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
- National Institute for Infectious Diseases L. Spallanzani, IRCCS, Via Portuense, 292, 00149, Rome, Italy
| | - Manuel López-Cabrera
- Tissue and Organ Homeostasis Program, Cell-Cell Communication and Inflammation Unit, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Consejo Superior de Investigaciones Científicas, 28049, Madrid, Spain
| | - Raffaele Strippoli
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
- National Institute for Infectious Diseases L. Spallanzani, IRCCS, Via Portuense, 292, 00149, Rome, Italy.
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Trionfetti F, Alonzi T, Bontempi G, Terri M, Battistelli C, Montaldo C, Repele F, Rotili D, Valente S, Zwergel C, Matusali G, Maggi F, Goletti D, Tripodi M, Mai A, Strippoli R. HDAC1-3 inhibition increases SARS-CoV-2 replication and productive infection in lung mesothelial and epithelial cells. Front Cell Infect Microbiol 2023; 13:1257683. [PMID: 38162580 PMCID: PMC10757821 DOI: 10.3389/fcimb.2023.1257683] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 10/30/2023] [Indexed: 01/03/2024] Open
Abstract
Background Despite the significant progress achieved in understanding the pathology and clinical management of SARS-CoV-2 infection, still pathogenic and clinical issues need to be clarified. Treatment with modulators of epigenetic targets, i.e., epidrugs, is a current therapeutic option in several cancers and could represent an approach in the therapy of viral diseases. Results Aim of this study was the analysis of the role of histone deacetylase (HDAC) inhibition in the modulation of SARS-CoV-2 infection of mesothelial cells (MCs).MeT5A cells, a pleura MC line, were pre-treated with different specific class I and IIb HDAC inhibitors. Unexpectedly, treatment with HDAC1-3 inhibitors significantly increased ACE2/TMPRSS2 expression, suggesting a role in favoring SARS-CoV-2 infection. We focused our analysis on the most potent ACE2/TMPRSS2 inducer among the inhibitors analysed, MS-275, a HDAC1-3 inhibitor. ACE2/TMPRSS2 expression was validated by Western Blot (WB) and immunofluorescence. The involvement of HDAC inhibition in receptor induction was confirmed by HDAC1/HDAC2 silencing. In accordance to the ACE2/TMPRSS2 expression data, MS-275 increased SARS-CoV-2 replication and virus propagation in Vero E6 cells.Notably, MS-275 was able to increase ACE2/TMPRSS2 expression and SARS-CoV-2 production, although to a lesser extent, also in the lung adenocarcinoma cell line Calu-3 cells.Mechanistically, treatment with MS-275 increased H3 and H4 histone acetylation at ACE2/TMPRSS2 promoters, increasing their transcription. Conclusion This study highlights a previously unrecognized effect of HDAC1-3 inhibition in increasing SARS-CoV-2 cell entry, replication and productive infection correlating with increased expression of ACE2 and TMPRSS2. These data, while adding basic insight into COVID-19 pathogenesis, warn for the use of HDAC inhibitors in SARS-CoV-2 patients.
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Affiliation(s)
- Flavia Trionfetti
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
- Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Tonino Alonzi
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, Rome, Italy
| | - Giulio Bontempi
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
- Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Michela Terri
- Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy
| | | | - Claudia Montaldo
- Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Federica Repele
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, Rome, Italy
| | - Dante Rotili
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy
| | - Clemens Zwergel
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy
| | - Giulia Matusali
- Laboratory of Virology, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Fabrizio Maggi
- Laboratory of Virology, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Delia Goletti
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, Rome, Italy
| | - Marco Tripodi
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy
- Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, Rome, Italy
| | - Raffaele Strippoli
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
- Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Rome, Italy
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Huang J, Zhang JL, Ang L, Li MC, Zhao M, Wang Y, Wu Q. Proposing a novel molecular subtyping scheme for predicting distant recurrence-free survival in breast cancer post-neoadjuvant chemotherapy with close correlation to metabolism and senescence. Front Endocrinol (Lausanne) 2023; 14:1265520. [PMID: 37900131 PMCID: PMC10602753 DOI: 10.3389/fendo.2023.1265520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 09/12/2023] [Indexed: 10/31/2023] Open
Abstract
Background High relapse rates remain a clinical challenge in the management of breast cancer (BC), with distant recurrence being a major driver of patient deterioration. To optimize the surveillance regimen for distant recurrence after neoadjuvant chemotherapy (NAC), we conducted a comprehensive analysis using bioinformatics and machine learning approaches. Materials and methods Microarray data were retrieved from the GEO database, and differential expression analysis was performed with the R package 'Limma'. We used the Metascape tool for enrichment analyses, and 'WGCNA' was utilized to establish co-expression networks, selecting the soft threshold power with the 'pickSoftThreshold' algorithm. We integrated ten machine learning algorithms and 101 algorithm combinations to identify key genes associated with distant recurrence in BC. Unsupervised clustering was performed with the R package 'ConsensusCluster Plus'. To further screen the key gene signature of residual cancer burden (RCB), multiple knockdown studies were analyzed with the Genetic Perturbation Similarity Analysis (GPSA) database. Single-cell RNA sequencing (scRNA-seq) analysis was conducted through the Tumour Immune Single-cell Hub (TISCH) database, and the XSum algorithm was used to screen candidate small molecule drugs based on the Connectivity Map (CMAP) database. Molecular docking processes were conducted using Schrodinger software. GMT files containing gene sets associated with metabolism and senescence were obtained from GSEA MutSigDB database. The GSVA score for each gene set across diverse samples was computed using the ssGSEA function implemented in the GSVA package. Results Our analysis, which combined Limma, WGCNA, and machine learning approaches, identified 16 RCB-relevant gene signatures influencing distant recurrence-free survival (DRFS) in BC patients following NAC. We then screened GATA3 as the key gene signature of high RCB index using GPSA analysis. A novel molecular subtyping scheme was developed to divide patients into two clusters (C1 and C2) with different distant recurrence risks. This molecular subtyping scheme was found to be closely associated with tumor metabolism and cellular senescence. Patients in cluster C2 had a poorer DRFS than those in cluster C1 (HR: 4.04; 95% CI: 2.60-6.29; log-rank test p < 0.0001). High GATA3 expression, high levels of resting mast cell infiltration, and a high proportion of estrogen receptor (ER)-positive patients contributed to better DRFS in cluster C1. We established a nomogram based on the N stage, RCB class, and molecular subtyping. The ROC curve for 5-year DRFS showed excellent predictive value (AUC=0.91, 95% CI: 0.95-0.86), with a C-index of 0.85 (95% CI: 0.81-0.90). Entinostat was identified as a potential small molecule compound to reverse high RCB after NAC. We also provided a comprehensive review of the EDCs exposures that potentially impact the effectiveness of NAC among BC patients. Conclusion This study established a molecular classification scheme associated with tumor metabolism and cancer cell senescence to predict RCB and DRFS in BC patients after NAC. Furthermore, GATA3 was identified and validated as a key gene associated with BC recurrence.
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Affiliation(s)
- Jin Huang
- Department of Pathology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jian-Lin Zhang
- Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lin Ang
- Department of Pathology, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
| | - Ming-Cong Li
- Department of Pathology, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
| | - Min Zhao
- Department of Pathology, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China
| | - Yao Wang
- Digestive Endoscopy Department, Jiangsu Provincial People’s Hospital, The First Afliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qiang Wu
- Department of Pathology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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Baek SY, Lee J, Kim T, Lee H, Choi HS, Park H, Koh M, Kim E, Jung ME, Iliopoulos D, Lee JY, Kim J, Lee S. Development of a novel histone deacetylase inhibitor unveils the role of HDAC11 in alleviating depression by inhibition of microglial activation. Biomed Pharmacother 2023; 166:115312. [PMID: 37567072 DOI: 10.1016/j.biopha.2023.115312] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/07/2023] [Accepted: 08/07/2023] [Indexed: 08/13/2023] Open
Abstract
Histone deacetylases (HDACs) are key epigenetic regulators and classified into four subtypes. Despite the various roles of each HDAC isoform, the lack of selective HDAC inhibitors has limited the elucidation of their roles in biological systems. HDAC11, the sole class-IV HDAC, is highly expressed in the brain, however, the role of HDAC11 in microglia is not fully understood. Based on the modification of MC1568, we developed a novel HDAC inhibitor, 5. Interestingly, 5 suppresses lipopolysaccharide-induced microglial activation by the initiation of autophagy and subsequent inhibition of nitric oxide production. Furthermore, we demonstrated that 5 significantly alleviates depression-like behavior by inhibiting microglial activation in mouse brain. Our discovery reveals that specific pharmacological regulation of HDAC11 induces autophagy and reactive nitrogen species balance in microglia for the first time, which makes HDAC11 a new therapeutic target for depressive disorder.
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Affiliation(s)
- Soo Yeon Baek
- Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, South Korea
| | - Jeehee Lee
- Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, South Korea; Department of HY-KIST Bio-convergence, Hanyang University, Seoul 04763, South Korea
| | - Taegwan Kim
- Department of Chemistry and Integrative Institute of Basic Science, Soongsil University, Seoul 06978, South Korea
| | - Hyelim Lee
- Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, South Korea
| | - Hoon-Seong Choi
- Research Animal Resources Center, Research Resources Division, Korea Institute of Science and Technology, Seoul 02792, South Korea
| | - Hahnbeom Park
- Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, South Korea
| | - Minseob Koh
- Department of Chemistry, Pusan National University, Busan 46241, South Korea
| | - Eunha Kim
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, South Korea
| | - Michael E Jung
- Department of Chemistry & Biochemistry, University of California at Los Angeles (UCLA), Los Angeles, CA 90095-1569, USA
| | - Dimitrios Iliopoulos
- Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, CA 90095, USA
| | - Jeong-Yeon Lee
- Department of Pathology, College of Medicine, Hanyang University, Seoul 04763, South Korea
| | - Jonghoon Kim
- Department of Chemistry and Integrative Institute of Basic Science, Soongsil University, Seoul 06978, South Korea.
| | - Sanghee Lee
- Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, South Korea; Department of HY-KIST Bio-convergence, Hanyang University, Seoul 04763, South Korea.
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Wu Z, Su J, Li FL, Chen T, Mayner J, Engler A, Ma S, Li Q, Guan KL. YAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis. Nat Commun 2023; 14:5916. [PMID: 37739954 PMCID: PMC10516997 DOI: 10.1038/s41467-023-41585-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 09/07/2023] [Indexed: 09/24/2023] Open
Abstract
Small cell lung cancer (SCLC) is highly lethal due to its prevalent metastasis. Most SCLCs have inactivating mutations in TP53 and RB1. We find that loss of YAP expression is key for SCLC cells to acquire rapid ameboid migration and high metastatic potential. YAP functions through its target genes CCN1/CCN2 to inhibit SCLC ameboid migration. RB1 mutation contributes to YAP transcriptional silencing via E2F7, which recruits the RCOR co-repressor complex to YAP promoter. We discover that benzamide family HDAC inhibitors stimulate YAP expression by inhibiting the RCOR-HDAC complex, thereby suppressing SCLC metastasis and improving survival in a mouse model. Our study unveils the molecular and cellular basis underlying SCLC's high metastatic potential, the previously unrecognized role of YAP in suppressing ameboid migration and tumor metastasis, and the mechanism of YAP transcription regulation involving E2F7, RCOR, and Sin3 HDAC. This study reveals a therapeutic potential of benzamides for SCLC treatment.
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Affiliation(s)
- Zhengming Wu
- Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Junhui Su
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Fu-Long Li
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Tao Chen
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Jaimie Mayner
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Adam Engler
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Shenghong Ma
- Wellcome Sanger Institute, Cambridge, CB10 1RQ, UK
| | - Qingquan Li
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China.
| | - Kun-Liang Guan
- Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA.
- School of Life Sciences, Westlake University, Hangzhou, 310030, China.
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Scumaci D, Zheng Q. Epigenetic meets metabolism: novel vulnerabilities to fight cancer. Cell Commun Signal 2023; 21:249. [PMID: 37735413 PMCID: PMC10512595 DOI: 10.1186/s12964-023-01253-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 08/01/2023] [Indexed: 09/23/2023] Open
Abstract
Histones undergo a plethora of post-translational modifications (PTMs) that regulate nucleosome and chromatin dynamics and thus dictate cell fate. Several evidences suggest that the accumulation of epigenetic alterations is one of the key driving forces triggering aberrant cellular proliferation, invasion, metastasis and chemoresistance pathways. Recently a novel class of histone "non-enzymatic covalent modifications" (NECMs), correlating epigenome landscape and metabolic rewiring, have been described. These modifications are tightly related to cell metabolic fitness and are able to impair chromatin architecture. During metabolic reprogramming, the high metabolic flux induces the accumulation of metabolic intermediate and/or by-products able to react with histone tails altering epigenome homeostasis. The accumulation of histone NECMs is a damaging condition that cancer cells counteracts by overexpressing peculiar "eraser" enzymes capable of removing these modifications preserving histones architecture. In this review we explored the well-established NECMs, emphasizing the role of their corresponding eraser enzymes. Additionally, we provide a parterre of drugs aiming to target those eraser enzymes with the intent to propose novel routes of personalized medicine based on the identification of epi-biomarkers which might be selectively targeted for therapy. Video Abstract.
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Affiliation(s)
- Domenica Scumaci
- Research Center On Advanced Biochemistry and Molecular Biology, Magna Græcia University of Catanzaro, 88100, Catanzaro, Italy.
- Department of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, 88100, Catanzaro, Italy.
| | - Qingfei Zheng
- Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
- Center for Cancer Metabolism, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
- Department of Biological Chemistry and Pharmacology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
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Pulya S, Himaja A, Paul M, Adhikari N, Banerjee S, Routholla G, Biswas S, Jha T, Ghosh B. Selective HDAC3 Inhibitors with Potent In Vivo Antitumor Efficacy against Triple-Negative Breast Cancer. J Med Chem 2023; 66:12033-12058. [PMID: 37660352 DOI: 10.1021/acs.jmedchem.3c00614] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
HDAC3 modulation shows promise for breast cancer, including triple-negative cases. Novel pyrazino-hydrazide-based HDAC3 inhibitors were designed and synthesized. Lead compound 4i exhibited potent HDAC3 inhibition (IC50 = 14 nM) with at least 121-fold selectivity. It demonstrated strong cytotoxicity against triple-negative breast cancer cells (IC50: 0.55 μM for 4T1, 0.74 μM for MDA-MB-231) with least normal cell toxicity. Metabolically stable 4i displayed a superior pharmacokinetic profile. A dose-dependent therapeutic efficacy of 4i was observed in a tumor-bearing mouse model. The biomarker analysis with tumor tissues displayed enhanced acetylation on Ac-H3K9, Ac-H3K27, and Ac-H4K12 compared to Ac-tubulin and Ac-SMC3 indicating HDAC3 selectivity of 4i in vivo. The immunoblotting study with tumor tissue showed upregulation of apoptotic proteins caspase-3, caspase-7, and cytochrome c and the downregulation of proliferation markers Bcl-2, CD44, EGFR, and Ki-67. Compound 4i represents a promising candidate for targeted breast cancer therapy, particularly for cases with triple-negative breast cancer.
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Affiliation(s)
- Sravani Pulya
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad 500078, India
| | - Ambati Himaja
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad 500078, India
| | - Milan Paul
- Nanomedicine Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad 500078, India
| | - Nilanjan Adhikari
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P.O. Box 17020, Kolkata, West Bengal 700032, India
| | - Suvankar Banerjee
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P.O. Box 17020, Kolkata, West Bengal 700032, India
| | - Ganesh Routholla
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad 500078, India
| | - Swati Biswas
- Nanomedicine Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad 500078, India
| | - Tarun Jha
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P.O. Box 17020, Kolkata, West Bengal 700032, India
| | - Balaram Ghosh
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad 500078, India
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Sammarco E, Manfredi F, Nuzzo A, Ferrari M, Bonato A, Salfi A, Serafin D, Zatteri L, Antonuzzo A, Galli L. Immune Checkpoint Inhibitor Rechallenge in Renal Cell Carcinoma: Current Evidence and Future Directions. Cancers (Basel) 2023; 15:3172. [PMID: 37370782 DOI: 10.3390/cancers15123172] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/11/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Immune checkpoint inhibitor-based therapies represent the current standard of care in the first-line treatment of advanced renal cell carcinoma. Despite a clear benefit in survival outcomes, a considerable proportion of patients experience disease progression; prospective data about second-line therapy after first-line treatment with immune checkpoint inhibitors are limited to small phase II studies. As with other solid tumors (such as melanoma and non-small cell lung cancer), preliminary data about the clinical efficacy of rechallenge of immunotherapy (alone or in combination with other drugs) in renal cell carcinoma are beginning to emerge. Nevertheless, the role of rechallenge in immunotherapy in this setting of disease remains unclear and cannot be considered a standard of care; currently some randomized trials are exploring this approach in patients with metastatic renal cell carcinoma. The aim of our review is to summarize main evidence available in the literature concerning immunotherapy rechallenge in renal carcinoma, especially focusing on biological rationale of resistance to immune checkpoint inhibitors, on the published data of clinical efficacy and on future perspectives.
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Affiliation(s)
- Enrico Sammarco
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Fiorella Manfredi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Amedeo Nuzzo
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Marco Ferrari
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Adele Bonato
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Alessia Salfi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Debora Serafin
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Luca Zatteri
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Andrea Antonuzzo
- Unit of Medical Oncology 1, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Luca Galli
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
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23
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Lin LC, Tu B, Song K, Liu ZY, Sun H, Zhou Y, Sha JM, Yang JJ, Zhang Y, Zhao JY, Tao H. Mitochondrial quality control in cardiac fibrosis: Epigenetic mechanisms and therapeutic strategies. Metabolism 2023:155626. [PMID: 37302693 DOI: 10.1016/j.metabol.2023.155626] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 06/05/2023] [Accepted: 06/05/2023] [Indexed: 06/13/2023]
Abstract
Cardiac fibrosis (CF) is considered an ultimate common pathway of a wide variety of heart diseases in response to diverse pathological and pathophysiological stimuli. Mitochondria are characterized as isolated organelles with a double-membrane structure, and they primarily contribute to and maintain highly dynamic energy and metabolic networks whose distribution and structure exert potent support for cellular properties and performance. Because the myocardium is a highly oxidative tissue with high energy demands to continuously pump blood, mitochondria are the most abundant organelles within mature cardiomyocytes, accounting for up to one-third of the total cell volume, and play an essential role in maintaining optimal performance of the heart. Mitochondrial quality control (MQC), including mitochondrial fusion, fission, mitophagy, mitochondrial biogenesis, and mitochondrial metabolism and biosynthesis, is crucial machinery that modulates cardiac cells and heart function by maintaining and regulating the morphological structure, function and lifespan of mitochondria. Certain investigations have focused on mitochondrial dynamics, including manipulating and maintaining the dynamic balance of energy demand and nutrient supply, and the resultant findings suggest that changes in mitochondrial morphology and function may contribute to bioenergetic adaptation during cardiac fibrosis and pathological remodeling. In this review, we discuss the function of epigenetic regulation and molecular mechanisms of MQC in the pathogenesis of CF and provide evidence for targeting MQC for CF. Finally, we discuss how these findings can be applied to improve the treatment and prevention of CF.
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Affiliation(s)
- Li-Chan Lin
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China
| | - Bin Tu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China
| | - Kai Song
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China
| | - Zhi-Yan Liu
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China
| | - He Sun
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China
| | - Yang Zhou
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China
| | - Ji-Ming Sha
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China
| | - Jing-Jing Yang
- Department of Clinical Pharmacy, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China.
| | - Ye Zhang
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China.
| | - Jian-Yuan Zhao
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China; Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, PR China.
| | - Hui Tao
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China; Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, PR China; Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, PR China.
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24
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D’Silva SZ, Singh M, Pinto AS. NK cell defects: implication in acute myeloid leukemia. Front Immunol 2023; 14:1112059. [PMID: 37228595 PMCID: PMC10203541 DOI: 10.3389/fimmu.2023.1112059] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 04/25/2023] [Indexed: 05/27/2023] Open
Abstract
Acute Myeloid Leukemia (AML) is a complex disease with rapid progression and poor/unsatisfactory outcomes. In the past few years, the focus has been on developing newer therapies for AML; however, relapse remains a significant problem. Natural Killer cells have strong anti-tumor potential against AML. This NK-mediated cytotoxicity is often restricted by cellular defects caused by disease-associated mechanisms, which can lead to disease progression. A stark feature of AML is the low/no expression of the cognate HLA ligands for the activating KIR receptors, due to which these tumor cells evade NK-mediated lysis. Recently, different Natural Killer cell therapies have been implicated in treating AML, such as the adoptive NK cell transfer, Chimeric antigen receptor-modified NK (CAR-NK) cell therapy, antibodies, cytokine, and drug treatment. However, the data available is scarce, and the outcomes vary between different transplant settings and different types of leukemia. Moreover, remission achieved by some of these therapies is only for a short time. In this mini-review, we will discuss the role of NK cell defects in AML progression, particularly the expression of different cell surface markers, the available NK cell therapies, and the results from various preclinical and clinical trials.
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Affiliation(s)
- Selma Z. D’Silva
- Transplant Immunology and Immunogenetics Lab, Advanced Centre for Treatment, Education and Research in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Meenakshi Singh
- Transplant Immunology and Immunogenetics Lab, Advanced Centre for Treatment, Education and Research in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Andrea S. Pinto
- Transplant Immunology and Immunogenetics Lab, Advanced Centre for Treatment, Education and Research in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
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25
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Luo G, Liu B, Fu T, Liu Y, Li B, Li N, Geng Q. The Role of Histone Deacetylases in Acute Lung Injury-Friend or Foe. Int J Mol Sci 2023; 24:ijms24097876. [PMID: 37175583 PMCID: PMC10178380 DOI: 10.3390/ijms24097876] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/04/2023] [Accepted: 04/14/2023] [Indexed: 05/15/2023] Open
Abstract
Acute lung injury (ALI), caused by intrapulmonary or extrapulmonary factors such as pneumonia, shock, and sepsis, eventually disrupts the alveolar-capillary barrier, resulting in diffuse pulmonary oedema and microatasis, manifested by refractory hypoxemia, and respiratory distress. Not only is ALI highly lethal, but even if a patient survives, there are also multiple sequelae. Currently, there is no better treatment than supportive care, and we urgently need to find new targets to improve ALI. Histone deacetylases (HDACs) are epigenetically important enzymes that, together with histone acetylases (HATs), regulate the acetylation levels of histones and non-histones. While HDAC inhibitors (HDACis) play a therapeutic role in cancer, inflammatory, and neurodegenerative diseases, there is also a large body of evidence suggesting the potential of HDACs as therapeutic targets in ALI. This review explores the unique mechanisms of HDACs in different cell types of ALI, including macrophages, pulmonary vascular endothelial cells (VECs), alveolar epithelial cells (AECs), and neutrophils.
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Affiliation(s)
- Guoqing Luo
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Bohao Liu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Tinglv Fu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Yi Liu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Boyang Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Ning Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
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26
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Barrier ML, Myszor IT, Sahariah P, Sigurdsson S, Carmena-Bargueño M, Pérez-Sánchez H, Gudmundsson GH. Aroylated phenylenediamine HO53 modulates innate immunity, histone acetylation and metabolism. Mol Immunol 2023; 155:153-164. [PMID: 36812763 DOI: 10.1016/j.molimm.2023.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 11/18/2022] [Accepted: 02/07/2023] [Indexed: 02/22/2023]
Abstract
In the current context of antibiotic resistance, the need to find alternative treatment strategies is urgent. Our research aimed to use synthetized aroylated phenylenediamines (APDs) to induce the expression of cathelicidin antimicrobial peptide gene (CAMP) to minimize the necessity of antibiotic use during infection. One of these compounds, HO53, showed promising results in inducing CAMP expression in bronchial epithelium cells (BCi-NS1.1 hereafter BCi). Thus, to decipher the cellular effects of HO53 on BCi cells, we performed RNA sequencing (RNAseq) analysis after 4, 8 and 24 h treatment of HO53. The number of differentially expressed transcripts pointed out an epigenetic modulation. Yet, the chemical structure and in silico modeling indicated HO53 as a histone deacetylase (HDAC) inhibitor. When exposed to a histone acetyl transferase (HAT) inhibitor, BCi cells showed a decreased expression of CAMP. Inversely, when treated with a specific HDAC3 inhibitor (RGFP996), BCi cells showed an increased expression of CAMP, indicating acetylation status in cells as determinant for the induction of the expression of the gene CAMP expression. Interestingly, a combination treatment with both HO53 and HDAC3 inhibitor RGFP966 leads to a further increase of CAMP expression. Moreover, HDAC3 inhibition by RGFP966 leads to increased expression of STAT3 and HIF1A, both previously demonstrated to be involved in pathways regulating CAMP expression. Importantly, HIF1α is considered as a master regulator in metabolism. A significant number of genes of metabolic enzymes were detected in our RNAseq data with enhanced expression conveying a shift toward enhanced glycolysis. Overall, we are demonstrating that HO53 might have a translational value against infections in the future through a mechanism leading to innate immunity strengthening involving HDAC inhibition and shifting the cells towards an immunometabolism, which further favors innate immunity activation.
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Affiliation(s)
- Marjorie Laurence Barrier
- Department of Life and Environmental Sciences, Biomedical Center, University of Iceland, Reykjavik, Iceland
| | - Iwona Teresa Myszor
- Department of Life and Environmental Sciences, Biomedical Center, University of Iceland, Reykjavik, Iceland
| | - Priyanka Sahariah
- Department of Life and Environmental Sciences, Biomedical Center, University of Iceland, Reykjavik, Iceland
| | - Snaevar Sigurdsson
- Department of Life and Environmental Sciences, Biomedical Center, University of Iceland, Reykjavik, Iceland
| | - Miguel Carmena-Bargueño
- Structural Bioinformatics and High Performance Computing Research Group (BIO-HPC), UCAM Universidad Católica de Murcia, Guadalupe, Spain
| | - Horacio Pérez-Sánchez
- Structural Bioinformatics and High Performance Computing Research Group (BIO-HPC), UCAM Universidad Católica de Murcia, Guadalupe, Spain
| | - Gudmundur Hrafn Gudmundsson
- Department of Life and Environmental Sciences, Biomedical Center, University of Iceland, Reykjavik, Iceland.
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27
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Urwanisch L, Unger MS, Sieberer H, Dang HH, Neuper T, Regl C, Vetter J, Schaller S, Winkler SM, Kerschbamer E, Weichenberger CX, Krenn PW, Luciano M, Pleyer L, Greil R, Huber CG, Aberger F, Horejs-Hoeck J. The Class IIA Histone Deacetylase (HDAC) Inhibitor TMP269 Downregulates Ribosomal Proteins and Has Anti-Proliferative and Pro-Apoptotic Effects on AML Cells. Cancers (Basel) 2023; 15:cancers15041039. [PMID: 36831382 PMCID: PMC9953883 DOI: 10.3390/cancers15041039] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 02/03/2023] [Accepted: 02/04/2023] [Indexed: 02/10/2023] Open
Abstract
Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by altered myeloid progenitor cell proliferation and differentiation. As in many other cancers, epigenetic transcriptional repressors such as histone deacetylases (HDACs) are dysregulated in AML. Here, we investigated (1) HDAC gene expression in AML patients and in different AML cell lines and (2) the effect of treating AML cells with the specific class IIA HDAC inhibitor TMP269, by applying proteomic and comparative bioinformatic analyses. We also analyzed cell proliferation, apoptosis, and the cell-killing capacities of TMP269 in combination with venetoclax compared to azacitidine plus venetoclax, by flow cytometry. Our results demonstrate significantly overexpressed class I and class II HDAC genes in AML patients, a phenotype which is conserved in AML cell lines. In AML MOLM-13 cells, TMP269 treatment downregulated a set of ribosomal proteins which are overexpressed in AML patients at the transcriptional level. TMP269 showed anti-proliferative effects and induced additive apoptotic effects in combination with venetoclax. We conclude that TMP269 exerts anti-leukemic activity when combined with venetoclax and has potential as a therapeutic drug in AML.
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Affiliation(s)
- Laura Urwanisch
- Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria
- Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria
| | - Michael Stefan Unger
- Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria
- Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria
| | - Helene Sieberer
- Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria
- Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria
| | - Hieu-Hoa Dang
- Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria
- Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria
| | - Theresa Neuper
- Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria
- Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria
| | - Christof Regl
- Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria
- Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria
| | - Julia Vetter
- Bioinformatics Research Group, University of Applied Sciences Upper Austria, Softwarepark 11, 4232 Hagenberg im Muehlkreis, Austria
| | - Susanne Schaller
- Bioinformatics Research Group, University of Applied Sciences Upper Austria, Softwarepark 11, 4232 Hagenberg im Muehlkreis, Austria
| | - Stephan M. Winkler
- Bioinformatics Research Group, University of Applied Sciences Upper Austria, Softwarepark 11, 4232 Hagenberg im Muehlkreis, Austria
| | - Emanuela Kerschbamer
- Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Via A. Volta 21, 39100 Bolzano, Italy
| | - Christian X. Weichenberger
- Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Via A. Volta 21, 39100 Bolzano, Italy
| | - Peter W. Krenn
- Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria
- Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria
| | - Michela Luciano
- Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria
- Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria
| | - Lisa Pleyer
- Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria
- IIIrd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Oncologic Center, Paracelsus Medical University, 5020 Salzburg, Austria
- Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, 5020 Salzburg, Austria
| | - Richard Greil
- Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria
- IIIrd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Oncologic Center, Paracelsus Medical University, 5020 Salzburg, Austria
- Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, 5020 Salzburg, Austria
| | - Christian G. Huber
- Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria
- Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria
| | - Fritz Aberger
- Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria
- Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria
| | - Jutta Horejs-Hoeck
- Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria
- Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria
- Correspondence: ; Tel.: +43-(0)662-8044-5709
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28
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Pal D, Sahu P, Mishra AK, Hagelgans A, Sukocheva O. Histone Deacetylase Inhibitors as Cognitive Enhancers and Modifiers of Mood and Behavior. Curr Drug Targets 2023; 24:728-750. [PMID: 36475351 DOI: 10.2174/1389450124666221207090108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 09/29/2022] [Accepted: 10/10/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Epigenetic regulation of gene signalling is one of the fundamental molecular mechanisms for the generation and maintenance of cellular memory. Histone acetylation is a common epigenetic mechanism associated with increased gene transcription in the central nervous system (CNS). Stimulation of gene transcription by histone acetylation is important for the development of CNS-based long-term memory. Histone acetylation is a target for cognitive enhancement via the application of histone deacetylase (HDAC) inhibitors. The promising potential of HDAC inhibitors has been observed in the treatment of several neurodevelopmental and neurodegenerative diseases. OBJECTIVE This study assessed the current state of HDAC inhibition as an approach to cognitive enhancement and treatment of neurodegenerative diseases. Our analysis provides insights into the mechanism of action of HDAC inhibitors, associated epigenetic priming, and describes the therapeutic success and potential complications after unsupervised use of the inhibitors. RESULTS AND CONCLUSION Several chromatin-modifying enzymes play key roles in the regulation of cognitive processes. The importance of HDAC signaling in the brain is highlighted in this review. Recent advancements in the field of cognitive epigenetics are supported by the successful development of various HDAC inhibitors, demonstrating effective treatment of mood-associated disorders. The current review discusses the therapeutic potential of HDAC inhibition and observed complications after mood and cognitive enhancement therapies.
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Affiliation(s)
- Dilipkumar Pal
- Department of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, C.G., 495 009, India
| | - Pooja Sahu
- Department of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, C.G., 495 009, India
| | | | - Albert Hagelgans
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Olga Sukocheva
- College of Nursing and Health Sciences, Flinders University of South Australia, Bedford Park, 5042, SA, Australia
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29
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Abdelsalam M, Ibrahim HS, Krauss L, Zessin M, Vecchio A, Hastreiter S, Schutkowski M, Schneider G, Sippl W. Development of Pyrazine-Anilinobenzamides as Histone Deacetylase HDAC1-3 Selective Inhibitors and Biological Testing Against Pancreas Cancer Cell Lines. Methods Mol Biol 2023; 2589:145-155. [PMID: 36255623 DOI: 10.1007/978-1-0716-2788-4_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Class I histone deacetylase (HDAC) enzymes are key regulators of cell proliferation and are frequently dysregulated in cancer cells. Here we describe the synthesis of a novel series of class-I selective HDAC inhibitors containing anilinobenzamide moieties as ZBG connected with a central (piperazin-1-yl)pyrazine moiety. Compounds were tested in vitro against class-I HDAC1, 2, and 3 isoforms. Some highly potent HDAC inhibitors were obtained and were tested in pancreatic cancer cells and showed promising activity. Moreover, we summarize how the growth-inhibitory effects of these compounds can be determined in murine pancreatic cancer cell lines.
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Affiliation(s)
- Mohamed Abdelsalam
- Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany
- Institute of Pharmacy, University of Alexandria, Alexandria, Egypt
| | - Hany S Ibrahim
- Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany
| | - Lukas Krauss
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
| | - Matthes Zessin
- Institute of Biochemistry, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany
| | - Anita Vecchio
- Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany
| | - Sieglinde Hastreiter
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
- Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany
| | - Mike Schutkowski
- Institute of Biochemistry, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany
| | - Günter Schneider
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
| | - Wolfgang Sippl
- Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany.
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30
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Bontempi G, Terri M, Garbo S, Montaldo C, Mariotti D, Bordoni V, Valente S, Zwergel C, Mai A, Marchetti A, Domenici A, Menè P, Battistelli C, Tripodi M, Strippoli R. Restoration of WT1/miR-769-5p axis by HDAC1 inhibition promotes MMT reversal in mesenchymal-like mesothelial cells. Cell Death Dis 2022; 13:965. [PMID: 36396626 PMCID: PMC9672101 DOI: 10.1038/s41419-022-05398-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 10/28/2022] [Accepted: 11/02/2022] [Indexed: 11/18/2022]
Abstract
Histone acetylation/deacetylation play an essential role in modifying chromatin structure and in regulating cell plasticity in eukaryotic cells. Therefore, histone deacetylase (HDAC) pharmacological inhibitors are promising tools in the therapy of fibrotic diseases and in cancer. Peritoneal fibrosis is a pathological process characterized by many cellular and molecular alterations, including the acquisition of invasive/pro-fibrotic abilities by mesothelial cells (MCs) through induction of mesothelial to mesenchymal transition (MMT). The aim of this study was to characterize the molecular mechanism of the antifibrotic role of HDAC1 inhibition. Specifically, treatment with MS-275, an HDAC1-3 inhibitor previously known to promote MMT reversal, induced the expression of several TGFBRI mRNA-targeting miRNAs. Among them, miR-769-5p ectopic expression was sufficient to promote MMT reversal and to limit MC migration and invasion, whereas miR-769-5p silencing further enhanced mesenchymal gene expression. These results were confirmed by HDAC1 genetic silencing. Interestingly, miR-769-5p silencing maintained mesenchymal features despite HDAC1 inhibition, thus indicating that it is necessary to drive MMT reversal induced by HDAC1 inhibition. Besides TGFBRI, miR-769-5p was demonstrated to target SMAD2/3 and PAI-1 expression directly. When analyzing molecular mechanisms underlying miR-769-5p expression, we found that the transcription factor Wilms' tumor 1 (WT1), a master gene controlling MC development, binds to the miR-769-5p promoter favoring its expression. Interestingly, both WT1 expression and binding to miR-769-5p promoter were increased by HDAC1 inhibition and attenuated by TGFβ1 treatment. Finally, we explored the significance of these observations in the cell-to-cell communication: we evaluated the ability of miR-769-5p to be loaded into extracellular vesicles (EVs) and to promote MMT reversal in recipient mesenchymal-like MCs. Treatment of fibrotic MCs with EVs isolated from miR-769-5p over-expressing MCs promoted the down-regulation of specific mesenchymal targets and the reacquisition of an epithelial-like morphology. In conclusion, we highlighted an HDAC1-WT1-miR-769-5p axis potentially relevant for therapies aimed at counteracting organ fibrosis.
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Affiliation(s)
- Giulio Bontempi
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L. Spallanzani, IRCCS, Via Portuense, 292, Rome, 00149, Italy
| | - Michela Terri
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L. Spallanzani, IRCCS, Via Portuense, 292, Rome, 00149, Italy
| | - Sabrina Garbo
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Claudia Montaldo
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L. Spallanzani, IRCCS, Via Portuense, 292, Rome, 00149, Italy
| | - Davide Mariotti
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L. Spallanzani, IRCCS, Via Portuense, 292, Rome, 00149, Italy
| | - Veronica Bordoni
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L. Spallanzani, IRCCS, Via Portuense, 292, Rome, 00149, Italy
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Clemens Zwergel
- Department of Drug Chemistry and Technologies, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Alessandra Marchetti
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Alessandro Domenici
- Renal Unit, Department of Clinical and Molecular Medicine, Sant'Andrea University Hospital, Sapienza University of Rome, 00189, Rome, Italy
| | - Paolo Menè
- Renal Unit, Department of Clinical and Molecular Medicine, Sant'Andrea University Hospital, Sapienza University of Rome, 00189, Rome, Italy
| | - Cecilia Battistelli
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Marco Tripodi
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L. Spallanzani, IRCCS, Via Portuense, 292, Rome, 00149, Italy.
| | - Raffaele Strippoli
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L. Spallanzani, IRCCS, Via Portuense, 292, Rome, 00149, Italy.
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31
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Dang F, Wei W. Targeting the acetylation signaling pathway in cancer therapy. Semin Cancer Biol 2022; 85:209-218. [PMID: 33705871 PMCID: PMC8423867 DOI: 10.1016/j.semcancer.2021.03.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/22/2021] [Accepted: 03/02/2021] [Indexed: 12/12/2022]
Abstract
Acetylation represents one of the major post-translational protein modifications, which introduces an acetyl functional group into amino acids such as the lysine residue to yield an acetate ester bond, neutralizing its positive charge. Regulation of protein functions by acetylation occurs in multiple ways, such as affecting protein stability, activity, localization, and interaction with other proteins or DNA. It has been well documented that the recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to the transcriptional machinery can modulate histone acetylation status, which is directly involved in the dynamic regulation of genes controlling cell proliferation and division. Dysregulation of gene expression is involved in tumorigenesis and aberrant activation of histone deacetylases has been reported in several types of cancer. Moreover, there is growing body of evidence showing that acetylation is widely involved in non-histone proteins to impact their roles in various cellular processes including tumorigenesis. As such, small molecular compounds inhibiting HAT or HDAC enzymatic activities have been developed and investigated for therapeutic purpose. Here we review the recent progress in our understanding of protein acetylation and discuss the therapeutic potential of targeting the acetylation signaling pathway in cancer.
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Affiliation(s)
- Fabin Dang
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
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32
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Yan A, Zhao Y, Zhang L, Liang X, Zhang X, Liang F, Nian S, Li X, Sun Z, Li K, Zhao YF. β-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes. Open Life Sci 2022; 17:856-864. [PMID: 36045720 PMCID: PMC9372706 DOI: 10.1515/biol-2022-0095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/02/2022] [Accepted: 05/09/2022] [Indexed: 11/15/2022] Open
Abstract
Fibroblast growth factor 21 (FGF21) is secreted by hepatocytes as a peptide hormone to regulate glucose and lipid metabolism. FGF21 promotes hepatic ketogenesis and increases ketone body utilization in starvation. Histones are the target molecules of nutrients in regulating hepatic metabolic homeostasis. However, the effect of ketone bodies on FGF21 expression and the involvement of histones in it is not clear yet. The present study observed the effects of β-hydroxybutyrate (β-OHB), the main physiological ketone body, on FGF21 expression in human hepatoma HepG2 cells in vitro and in mice in vivo, and the role of histone deacetylases (HDACs) in β-OHB-regulated FGF21 expression was investigated. The results showed that β-OHB significantly upregulated FGF21 gene expression and increased FGF21 protein levels while it inhibited HDACs’ activity in HepG2 cells. HDACs’ inhibition by entinostat upregulated FGF21 expression and eliminated β-OHB-stimulated FGF21 expression in HepG2 cells. Intraperitoneal injections of β-OHB in mice resulted in the elevation of serum β-OHB and the inhibition of hepatic HDACs’ activity. Meanwhile, hepatic FGF21 expression and serum FGF21 levels were significantly increased in β-OHB-treated mice compared with the control. It is suggested that β-OHB upregulates FGF21 expression through inhibition of HDACs’ activity in hepatocytes.
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Affiliation(s)
- Aili Yan
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, 710021, China
| | - Yanyan Zhao
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, 710021, China
| | - Lijun Zhang
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, 710021, China
| | - Xiangyan Liang
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, 710021, China
| | - Xiaochun Zhang
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, 710021, China
| | - Fenli Liang
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, 710021, China
| | - Shen Nian
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, 710021, China
| | - Xinhua Li
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, 710021, China
| | - Zhuo Sun
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, 710021, China
| | - Ke Li
- Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, 710021, China
| | - Yu-Feng Zhao
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, 710021, China
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33
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Schirripa A, Sexl V, Kollmann K. Cyclin-dependent kinase inhibitors in malignant hematopoiesis. Front Oncol 2022; 12:916682. [PMID: 36033505 PMCID: PMC9403899 DOI: 10.3389/fonc.2022.916682] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
The cell-cycle is a tightly orchestrated process where sequential steps guarantee cellular growth linked to a correct DNA replication. The entire cell division is controlled by cyclin-dependent kinases (CDKs). CDK activation is balanced by the activating cyclins and CDK inhibitors whose correct expression, accumulation and degradation schedule the time-flow through the cell cycle phases. Dysregulation of the cell cycle regulatory proteins causes the loss of a controlled cell division and is inevitably linked to neoplastic transformation. Due to their function as cell-cycle brakes, CDK inhibitors are considered as tumor suppressors. The CDK inhibitors p16INK4a and p15INK4b are among the most frequently altered genes in cancer, including hematopoietic malignancies. Aberrant cell cycle regulation in hematopoietic stem cells (HSCs) bears severe consequences on hematopoiesis and provokes hematological disorders with a broad array of symptoms. In this review, we focus on the importance and prevalence of deregulated CDK inhibitors in hematological malignancies.
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34
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Pulya S, Patel T, Paul M, Adhikari N, Banerjee S, Routholla G, Biswas S, Jha T, Ghosh B. Selective inhibition of histone deacetylase 3 by novel hydrazide based small molecules as therapeutic intervention for the treatment of cancer. Eur J Med Chem 2022; 238:114470. [DOI: 10.1016/j.ejmech.2022.114470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/14/2022] [Accepted: 05/15/2022] [Indexed: 11/25/2022]
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35
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Di Bello E, Noce B, Fioravanti R, Zwergel C, Valente S, Rotili D, Fianco G, Trisciuoglio D, Mourão MM, Sales P, Lamotte S, Prina E, Späth GF, Häberli C, Keiser J, Mai A. Effects of Structurally Different HDAC Inhibitors against Trypanosoma cruzi, Leishmania, and Schistosoma mansoni. ACS Infect Dis 2022; 8:1356-1366. [PMID: 35732073 PMCID: PMC9274761 DOI: 10.1021/acsinfecdis.2c00232] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
![]()
Neglected tropical
diseases (NTDs), including trypanosomiasis,
leishmaniasis, and schistosomiasis, result in a significant burden
in terms of morbidity and mortality worldwide every year. Current
antiparasitic drugs suffer from several limitations such as toxicity,
no efficacy toward all of the forms of the parasites’ life
cycle, and/or induction of resistance. Histone-modifying enzymes play
a crucial role in parasite growth and survival; thus, the use of epigenetic
drugs has been suggested as a strategy for the treatment of NTDs.
We tested structurally different HDACi 1–9, chosen from our in-house library or newly synthesized,
against Trypanosoma cruzi,
Leishmania spp, and Schistosoma mansoni. Among them, 4 emerged as the most potent against all
of the tested parasites, but it was too toxic against host cells,
hampering further studies. The retinoic 2′-aminoanilide 8 was less potent than 4 in all parasitic assays,
but as its toxicity is considerably lower, it could be the starting
structure for further development. In T. cruzi, compound 3 exhibited a single-digit micromolar inhibition of parasite
growth combined with moderate toxicity. In S. mansoni, 4’s close analogs 17–20 were tested in new transformed schistosomula (NTS) and
adult worms displaying high death induction against both parasite
forms. Among them, 17 and 19 exhibited very
low toxicity in human retinal pigment epithelial (RPE) cells, thus
being promising compounds for further optimization.
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Affiliation(s)
- Elisabetta Di Bello
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Beatrice Noce
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Rossella Fioravanti
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Clemens Zwergel
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Dante Rotili
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Giulia Fianco
- Institute of Molecular Biology and Pathology, National Research Council (CNR), Via degli Apuli 4, 00185 Rome, Italy
| | - Daniela Trisciuoglio
- Institute of Molecular Biology and Pathology, National Research Council (CNR), Via degli Apuli 4, 00185 Rome, Italy
| | - Marina M Mourão
- Instituto René Rachou, Fundação Oswaldo Cruz, Avenida Augusto de Lima, 1715, 30190-002 Belo Horizonte, Brazil
| | - Policarpo Sales
- Instituto René Rachou, Fundação Oswaldo Cruz, Avenida Augusto de Lima, 1715, 30190-002 Belo Horizonte, Brazil
| | - Suzanne Lamotte
- Institut Pasteur, Université Paris Cité, INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, 25-28 Rue du Docteur Roux, 75015 Paris, France
| | - Eric Prina
- Institut Pasteur, Université Paris Cité, INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, 25-28 Rue du Docteur Roux, 75015 Paris, France
| | - Gerald F Späth
- Institut Pasteur, Université Paris Cité, INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, 25-28 Rue du Docteur Roux, 75015 Paris, France
| | - Cécile Häberli
- Swiss Tropical and Public Health Institute, 4002 Allschwil, Switzerland.,University of Basel, Peterspl. 1, 4001 Basel, Switzerland
| | - Jennifer Keiser
- Swiss Tropical and Public Health Institute, 4002 Allschwil, Switzerland.,University of Basel, Peterspl. 1, 4001 Basel, Switzerland
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy.,Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
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36
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Chen Q, Yang B, Liu X, Zhang XD, Zhang L, Liu T. Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents. Am J Cancer Res 2022; 12:4935-4948. [PMID: 35836809 PMCID: PMC9274749 DOI: 10.7150/thno.73223] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 05/23/2022] [Indexed: 01/12/2023] Open
Abstract
The histone acetyltransferases CBP and p300, often referred to as CBP/p300 due to their sequence homology and functional overlap and co-operation, are emerging as critical drivers of oncogenesis in the past several years. CBP/p300 induces histone H3 lysine 27 acetylation (H3K27ac) at target gene promoters, enhancers and super-enhancers, thereby activating gene transcription. While earlier studies indicate that CBP/p300 deletion/loss can promote tumorigenesis, CBP/p300 have more recently been shown to be over-expressed in cancer cells and drug-resistant cancer cells, activate oncogene transcription and induce cancer cell proliferation, survival, tumorigenesis, metastasis, immune evasion and drug-resistance. Small molecule CBP/p300 histone acetyltransferase inhibitors, bromodomain inhibitors, CBP/p300 and BET bromodomain dual inhibitors and p300 protein degraders have recently been discovered. The CBP/p300 inhibitors and degraders reduce H3K27ac, down-regulate oncogene transcription, induce cancer cell growth inhibition and cell death, activate immune response, overcome drug resistance and suppress tumor progression in vivo. In addition, CBP/p300 inhibitors enhance the anticancer efficacy of chemotherapy, radiotherapy and epigenetic anticancer agents, including BET bromodomain inhibitors; and the combination therapies exert substantial anticancer effects in mouse models of human cancers including drug-resistant cancers. Currently, two CBP/p300 inhibitors are under clinical evaluation in patients with advanced and drug-resistant solid tumors or hematological malignancies. In summary, CBP/p300 have recently been identified as critical tumorigenic drivers, and CBP/p300 inhibitors and protein degraders are emerging as promising novel anticancer agents for clinical translation.
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Affiliation(s)
- Qingjuan Chen
- Department of Oncology, 3201 Hospital of Xi'an Jiaotong University Health Science Center, Hanzhong, Shaanxi 723000, China
| | - Binhui Yang
- Department of Oncology, 3201 Hospital of Xi'an Jiaotong University Health Science Center, Hanzhong, Shaanxi 723000, China
| | - Xiaochen Liu
- Department of Oncology, 3201 Hospital of Xi'an Jiaotong University Health Science Center, Hanzhong, Shaanxi 723000, China
| | - Xu D. Zhang
- School of Medicine and Public Health, Priority Research Centre for Cancer Research, University of Newcastle, Callaghan, Newcastle, NSW 2308, Australia.,Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.,✉ Corresponding authors: E-mail: (Xu D. Zhang), (Lirong Zhang); (Tao Liu)
| | - Lirong Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.,✉ Corresponding authors: E-mail: (Xu D. Zhang), (Lirong Zhang); (Tao Liu)
| | - Tao Liu
- Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.,Children's Cancer Institute Australia, Randwick, Sydney, NSW 2031, Australia.,School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia.,✉ Corresponding authors: E-mail: (Xu D. Zhang), (Lirong Zhang); (Tao Liu)
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37
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Liu J, Li JN, Wu H, Liu P. The Status and Prospects of Epigenetics in the Treatment of Lymphoma. Front Oncol 2022; 12:874645. [PMID: 35463343 PMCID: PMC9033274 DOI: 10.3389/fonc.2022.874645] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 03/17/2022] [Indexed: 12/12/2022] Open
Abstract
The regulation of gene transcription by epigenetic modifications is closely related to many important life processes and is a hot research topic in the post-genomic era. Since the emergence of international epigenetic research in the 1990s, scientists have identified a variety of chromatin-modifying enzymes and recognition factors, and have systematically investigated their three-dimensional structures, substrate specificity, and mechanisms of enzyme activity regulation. Studies of the human tumor genome have revealed the close association of epigenetic factors with various malignancies, and we have focused more on mutations in epigenetically related regulatory enzymes and regulatory recognition factors in lymphomas. A number of studies have shown that epigenetic alterations are indeed widespread in the development and progression of lymphoma and understanding these mechanisms can help guide clinical efforts. In contrast to chemotherapy which induces cytotoxicity, epigenetic therapy has the potential to affect multiple cellular processes simultaneously, by reprogramming cells to achieve a therapeutic effect in lymphoma. Epigenetic monotherapy has shown promising results in previous clinical trials, and several epigenetic agents have been approved for use in the treatment of lymphoma. In addition, epigenetic therapies in combination with chemotherapy and/or immunotherapy have been used in various clinical trials. In this review, we present several important epigenetic modalities of regulation associated with lymphoma, summarize the corresponding epigenetic drugs in lymphoma, and look at the future of epigenetic therapies in lymphoma.
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Affiliation(s)
- Jiaxin Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jia-Nan Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Hongyu Wu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Panpan Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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38
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Upregulation of p75NTR by Histone Deacetylase Inhibitors Sensitizes Human Neuroblastoma Cells to Targeted Immunotoxin-Induced Apoptosis. Int J Mol Sci 2022; 23:ijms23073849. [PMID: 35409209 PMCID: PMC8998832 DOI: 10.3390/ijms23073849] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 03/29/2022] [Accepted: 03/29/2022] [Indexed: 12/22/2022] Open
Abstract
Histone deacetylase (HDAC) inhibitors are novel chemotherapy agents with potential utility in the treatment of neuroblastoma, the most frequent solid tumor of childhood. Previous studies have shown that the exposure of human neuroblastoma cells to some HDAC inhibitors enhanced the expression of the common neurotrophin receptor p75NTR. In the present study we investigated whether the upregulation of p75NTR could be exploited to render neuroblastoma cells susceptible to the cytotoxic action of an anti-p75NTR antibody conjugated to the toxin saporin-S6 (p75IgG-Sap). We found that two well-characterized HDAC inhibitors, valproic acid (VPA) and entinostat, were able to induce a strong expression of p75NTR in different human neuroblastoma cell lines but not in other cells, with entinostat, displaying a greater efficacy than VPA. Cell pretreatment with entinostat enhanced p75NTR internalization and intracellular saporin-S6 delivery following p75IgG-Sap exposure. The addition of p75IgG-Sap had no effect on vehicle-pretreated cells but potentiated the apoptotic cell death that was induced by entinostat. In three-dimensional neuroblastoma cell cultures, the subsequent treatment with p75IgG-Sap enhanced the inhibition of spheroid growth and the impairment of cell viability that was produced by entinostat. In athymic mice bearing neuroblastoma xenografts, chronic treatment with entinostat increased the expression of p75NTR in tumors but not in liver, kidney, heart, and cerebellum. The administration of p75IgG-Sap induced apoptosis only in tumors of mice that were pretreated with entinostat. These findings define a novel experimental strategy to selectively eliminate neuroblastoma cells based on the sequential treatment with entinostat and a toxin-conjugated anti-p75NTR antibody.
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Barone S, Cassese E, Alfano AI, Brindisi M, Summa V. Chasing a Breath of Fresh Air in Cystic Fibrosis (CF): Therapeutic Potential of Selective HDAC6 Inhibitors to Tackle Multiple Pathways in CF Pathophysiology. J Med Chem 2022; 65:3080-3097. [PMID: 35148101 PMCID: PMC8883472 DOI: 10.1021/acs.jmedchem.1c02067] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
![]()
Compelling new support
has been provided for histone deacetylase
isoform 6 (HDAC6) as a common thread in the generation of the dysregulated
proinflammatory and fibrotic phenotype in cystic fibrosis (CF). HDAC6
also plays a crucial role in bacterial clearance or killing as a direct
consequence of its effects on CF immune responses. Inhibiting HDAC6
functions thus eventually represents an innovative and effective strategy
to tackle multiple aspects of CF-associated lung disease. In this
Perspective, we not only showcase the latest evidence linking HDAC(6)
activity and expression with CF phenotype but also track the new dawn
of HDAC(6) modulators in CF and explore potentialities and future
perspectives in the field.
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Affiliation(s)
- Simona Barone
- Department of Pharmacy, Department of Excellence 2018-2022, School of Medicine and Surgery, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy
| | - Emilia Cassese
- Department of Pharmacy, Department of Excellence 2018-2022, School of Medicine and Surgery, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy
| | - Antonella Ilenia Alfano
- Department of Pharmacy, Department of Excellence 2018-2022, School of Medicine and Surgery, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy
| | - Margherita Brindisi
- Department of Pharmacy, Department of Excellence 2018-2022, School of Medicine and Surgery, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy
| | - Vincenzo Summa
- Department of Pharmacy, Department of Excellence 2018-2022, School of Medicine and Surgery, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy
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40
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Yoshida Y, Yuki K, Dan S, Yamazaki K, Noda M. Suppression of tumor metastasis by a RECK-activating small molecule. Sci Rep 2022; 12:2319. [PMID: 35149728 PMCID: PMC8837781 DOI: 10.1038/s41598-022-06288-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
RECK encodes a membrane-anchored protease-regulator which is often downregulated in a wide variety of cancers, and reduced RECK expression often correlates with poorer prognoses. In mouse models, forced expression of RECK in tumor xenografts results in suppression of tumor angiogenesis, invasion, and metastasis. RECK mutations, however, are rare in cancer genomes, suggesting that agents that re-activate dormant RECK may be of clinical value. We found a potent RECK-inducer, DSK638, that inhibits spontaneous lung metastasis in our mouse xenograft model. Induction of RECK expression involves SP1 sites in its promoter and may be mediated by KLF2. DSK638 also upregulates MXI1, an endogenous MYC-antagonist, and inhibition of metastasis by DSK638 is dependent on both RECK and MXI1. This study demonstrates the utility of our approach (using a simple reporter assay followed by multiple phenotypic assays) and DSK638 itself (as a reference compound) in finding potential metastasis-suppressing drugs.
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Affiliation(s)
- Yoko Yoshida
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, 606-8501, Japan. .,Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, 135-8550, Japan.
| | - Kanako Yuki
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Shingo Dan
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, 135-8550, Japan
| | - Kanami Yamazaki
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, 135-8550, Japan
| | - Makoto Noda
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, 606-8501, Japan.
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41
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Kelava I, Chiaradia I, Pellegrini L, Kalinka AT, Lancaster MA. Androgens increase excitatory neurogenic potential in human brain organoids. Nature 2022; 602:112-116. [PMID: 35046577 PMCID: PMC7612328 DOI: 10.1038/s41586-021-04330-4] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 12/09/2021] [Indexed: 12/15/2022]
Abstract
The biological basis of male-female brain differences has been difficult to elucidate in humans. The most notable morphological difference is size, with male individuals having on average a larger brain than female individuals1,2, but a mechanistic understanding of how this difference arises remains unknown. Here we use brain organoids3 to show that although sex chromosomal complement has no observable effect on neurogenesis, sex steroids-namely androgens-lead to increased proliferation of cortical progenitors and an increased neurogenic pool. Transcriptomic analysis and functional studies demonstrate downstream effects on histone deacetylase activity and the mTOR pathway. Finally, we show that androgens specifically increase the neurogenic output of excitatory neuronal progenitors, whereas inhibitory neuronal progenitors are not increased. These findings reveal a role for androgens in regulating the number of excitatory neurons and represent a step towards understanding the origin of sex-related brain differences in humans.
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Affiliation(s)
- Iva Kelava
- Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
- Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
| | - Ilaria Chiaradia
- Medical Research Council Laboratory of Molecular Biology, Cambridge, UK
| | - Laura Pellegrini
- Medical Research Council Laboratory of Molecular Biology, Cambridge, UK
| | - Alex T Kalinka
- Milner Therapeutics Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
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Sunil AA, Skaria T. Novel regulators of airway epithelial barrier function during inflammation: potential targets for drug repurposing. Expert Opin Ther Targets 2022; 26:119-132. [PMID: 35085478 DOI: 10.1080/14728222.2022.2035720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Endogenous inflammatory signaling molecules resulting from deregulated immune responses, can impair airway epithelial barrier function and predispose individuals with airway inflammatory diseases to exacerbations and lung infections. Targeting the specific endogenous factors disrupting the airway barrier therefore has the potential to prevent disease exacerbations without affecting the protective immune responses. AREAS COVERED Here, we review the endogenous factors and specific mechanisms disrupting airway epithelial barrier during inflammation and reflect on whether these factors can be specifically targeted by repurposed existing drugs. Literature search was conducted using PubMed, drug database of US FDA and European Medicines Agency until and including September 2021. EXPERT OPINION IL-4 and IL-13 signaling are the major pathways disrupting the airway epithelial barrier during airway inflammation. However, blocking IL-4/IL-13 signaling may adversely affect protective immune responses and increase susceptibility of host to infections. An alternate approach to modulate airway epithelial barrier function involves targeting specific downstream component of IL-4/IL-13 signaling or different inflammatory mediators responsible for regulation of airway epithelial barrier. Airway epithelium-targeted therapy using inhibitors of HDAC, HSP90, MIF, mTOR, IL-17A and VEGF may be a potential strategy to prevent airway epithelial barrier dysfunction in airway inflammatory diseases.
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Affiliation(s)
- Ahsan Anjoom Sunil
- School of Biotechnology, National Institute of Technology Calicut, Calicut, Kerala, India
| | - Tom Skaria
- School of Biotechnology, National Institute of Technology Calicut, Calicut, Kerala, India
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Feng Y, Lu Y, Li J, Zhang H, Li Z, Feng H, Deng X, Liu D, Shi T, Jiang W, He Y, Zhang J, Wang Z. Design, synthesis and biological evaluation of novel o-aminobenzamide derivatives as potential anti-gastric cancer agents in vitro and in vivo. Eur J Med Chem 2022; 227:113888. [PMID: 34628244 DOI: 10.1016/j.ejmech.2021.113888] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 09/27/2021] [Accepted: 09/29/2021] [Indexed: 12/13/2022]
Abstract
Although gastric cancer has become a major public health problem, oral agents applied in clinics for gastric cancer therapy are scarce. Therefore, to explore new oral chemical entities with high efficiency and low toxicity, 41 o-aminobenzamide derivatives based on the scaffolds of MS-275 and SAHA were designed, synthesized, and evaluated for their anti-gastric cancer abilities in vitro and in vivo. Structure-activity relationships were discussed, leading to the identification of compounds F8 (IC50 = 0.28 μM against HGC-27 cell) and T9 (IC50 = 1.84 μM against HGC-27 cell) with improved cytotoxicity, anti-gastric cancer proliferation potency, induction of cell apoptosis and cell cycle arrest ability, inhibition of cell migration and invasion. What is worth mentioning is that compound F8 was more efficient and less toxic than the positive drug capecitabine in vivo on the HGC-27-xenograft model. Meanwhile, compound F8 exhibited suitable pharmacokinetic properties and less acute toxicity (LD50 > 1000 mg/kg). Besides, western blotting analysis, IHC analysis, differentially expressed proteins analysis and ABPP experiment indicated that compound F8 could modulate molecular pathways involved in apoptosis and cell cycle progression. Consequently, compound F8 is a strong candidate for the development of human gastric cancer therapy.
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Affiliation(s)
- Yiyue Feng
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Yingmei Lu
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Junfang Li
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Honghua Zhang
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Zhao Li
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Hanzhong Feng
- Ministry of Education, Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Xuemei Deng
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Dan Liu
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Tao Shi
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Weifan Jiang
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Yongxing He
- Ministry of Education, Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China.
| | - Jian Zhang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China.
| | - Zhen Wang
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
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Routholla G, Pulya S, Patel T, Adhikari N, Abdul Amin S, Paul M, Bhagavatula S, Biswas S, Jha T, Ghosh B. Design, synthesis and binding mode of interaction of novel small molecule o-hydroxy benzamides as HDAC3-selective inhibitors with promising antitumor effects in 4T1-Luc breast cancer xenograft model. Bioorg Chem 2021; 117:105446. [PMID: 34717237 DOI: 10.1016/j.bioorg.2021.105446] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 10/18/2021] [Indexed: 01/24/2023]
Abstract
Histone deacetylase 3 (HDAC3) is one of the most promising targets to develop anticancer therapeutics. In continuation of our quest for selective HDAC3 inhibitors, a series of small molecules having o-hydroxy benzamide as the novel zinc binding group (ZBG) has been introduced for the first time that can be able to produce good HDAC3-selectivity over other HDACs. The most promising HDAC3 inhibitors, 11a and 12b, displayed promising in vitro anticancer activities with less toxicity to normal kidney cells. These compounds significantly upregulate histone acetylation and induce apoptosis with a G2/M phase arrest in B16F10 cells. Compound 11a exhibited potent antitumor efficacy in 4T1-Luc breast cancer xenograft mouse model in female Balb/c mice. It also showed significant tumor growth suppression with no general toxicity and extended survival rates post-tumor resection. It significantly induced higher ROS generation, leading to apoptosis. No considerable toxicity was noticed in major organs isolated from the compound 11a-treated mice. Compound 11a also induced the upregulation of acH3K9, acH4K12, caspase-3 and caspase-7 as analyzed by immunoblotting with treated tumor tissue. Overall, HDAC3 selective inhibitor 11a might be a potential lead for the clinical translation as an emerging drug candidate.
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Affiliation(s)
- Ganesh Routholla
- Epigenetic Research Laboratory, Department of Pharmacy, BITS-Pilani, Hyderabad Campus, Shamirpet, Hyderabad 500078, India
| | - Sravani Pulya
- Epigenetic Research Laboratory, Department of Pharmacy, BITS-Pilani, Hyderabad Campus, Shamirpet, Hyderabad 500078, India
| | - Tarun Patel
- Epigenetic Research Laboratory, Department of Pharmacy, BITS-Pilani, Hyderabad Campus, Shamirpet, Hyderabad 500078, India
| | - Nilanjan Adhikari
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P. O. Box 17020, Jadavpur University, Kolkata 700032, West Bengal, India
| | - Sk Abdul Amin
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P. O. Box 17020, Jadavpur University, Kolkata 700032, West Bengal, India
| | - Milan Paul
- Nanomedicine Research Laboratory, Department of Pharmacy, BITS-Pilani, Hyderabad Campus, Shamirpet, Hyderabad 500078, India
| | - Srividya Bhagavatula
- Epigenetic Research Laboratory, Department of Pharmacy, BITS-Pilani, Hyderabad Campus, Shamirpet, Hyderabad 500078, India
| | - Swati Biswas
- Nanomedicine Research Laboratory, Department of Pharmacy, BITS-Pilani, Hyderabad Campus, Shamirpet, Hyderabad 500078, India
| | - Tarun Jha
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P. O. Box 17020, Jadavpur University, Kolkata 700032, West Bengal, India.
| | - Balaram Ghosh
- Epigenetic Research Laboratory, Department of Pharmacy, BITS-Pilani, Hyderabad Campus, Shamirpet, Hyderabad 500078, India.
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MS-275 (Entinostat) Promotes Radio-Sensitivity in PAX3-FOXO1 Rhabdomyosarcoma Cells. Int J Mol Sci 2021; 22:ijms221910671. [PMID: 34639012 PMCID: PMC8508838 DOI: 10.3390/ijms221910671] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 09/24/2021] [Accepted: 09/27/2021] [Indexed: 12/26/2022] Open
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. About 25% of RMS expresses fusion oncoproteins such as PAX3/PAX7-FOXO1 (fusion-positive, FP) while fusion-negative (FN)-RMS harbors RAS mutations. Radiotherapy (RT) plays a crucial role in local control but metastatic RMS is often radio-resistant. HDAC inhibitors (HDACi) radio-sensitize different cancer cells types. Thus, we evaluated MS-275 (Entinostat), a Class I and IV HDACi, in combination with RT on RMS cells in vitro and in vivo. MS-275 reversibly hampered cell survival in vitro in FN-RMS RD (RASmut) and irreversibly in FP-RMS RH30 cell lines down-regulating cyclin A, B, and D1, up-regulating p21 and p27 and reducing ERKs activity, and c-Myc expression in RD and PI3K/Akt/mTOR activity and N-Myc expression in RH30 cells. Further, MS-275 and RT combination reduced colony formation ability of RH30 cells. In both cell lines, co-treatment increased DNA damage repair inhibition and reactive oxygen species formation, down-regulated NRF2, SOD, CAT and GPx4 anti-oxidant genes and improved RT ability to induce G2 growth arrest. MS-275 inhibited in vivo growth of RH30 cells and completely prevented the growth of RT-unresponsive RH30 xenografts when combined with radiation. Thus, MS-275 could be considered as a radio-sensitizing agent for the treatment of intrinsically radio-resistant PAX3-FOXO1 RMS.
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Maemoto Y, Shimizu Y, Katoh R, Ito A. Naturally occurring small molecule compounds that target histone deacetylases and their potential applications in cancer therapy. J Antibiot (Tokyo) 2021; 74:667-676. [PMID: 34426659 DOI: 10.1038/s41429-021-00459-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/08/2021] [Accepted: 05/10/2021] [Indexed: 02/06/2023]
Abstract
Epigenetics is defined as the heritable alteration of gene expression without change to the DNA sequence. Epigenetic abnormalities play a role in various diseases, including cancer. Epigenetic regulation of gene expression occurs through histone chemical modifications and DNA methylation. Lysine acetylation is one of the major histone chemical modifications essential for epigenetic gene expression. Histone acetylation is reversibly regulated by histone acetyltransferases and histone deacetylases, which are molecular targets for cancer therapy. There has been an explosion of research in epigenetic-related drug discovery, and accordingly many small molecule compounds have been developed. Notably, several small molecule inhibitors of histone deacetylases have been approved for the treatment of cancer. This review will introduce natural products, their derivative inhibitors of histone deacetylases, and their clinical development.
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Affiliation(s)
- Yuki Maemoto
- School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Yuki Shimizu
- School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Ryu Katoh
- School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Akihiro Ito
- School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
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Carraway HE, Sawalha Y, Gojo I, Lee MJ, Lee S, Tomita Y, Yuno A, Greer J, Smith BD, Pratz KW, Levis MJ, Gore SD, Ghosh N, Dezern A, Blackford AL, Baer MR, Gore L, Piekarz R, Trepel JB, Karp JE. Phase 1 study of the histone deacetylase inhibitor entinostat plus clofarabine for poor-risk Philadelphia chromosome-negative (newly diagnosed older adults or adults with relapsed refractory disease) acute lymphoblastic leukemia or biphenotypic leukemia. Leuk Res 2021; 110:106707. [PMID: 34563945 DOI: 10.1016/j.leukres.2021.106707] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 08/22/2021] [Accepted: 09/08/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Despite advances in immunotherapies, the prognosis for adults with Philadelphia chromosome-negative, newly diagnosed (ND) or relapsed/refractory (R/R) acute lymphoblastic leukemia/acute biphenotypic leukemia (ALL/ABL) remains poor. The benzamide derivative entinostat inhibits histone deacetylase and induces histone hyperacetylation. The purine nucleoside analogue clofarabine is FDA-approved for R/R ALL in children 1-21 years of age. Low doses of clofarabine have been reported to induce DNA hypomethylation. We conducted a phase 1 study of low dose clofarabine with escalating doses of entinostat in adults with ND or R/R ALL/ABL. EXPERIMENTAL DESIGN Adults ≥60 years with ND ALL/ABL or ≥21 years with R/R ALL/ABL received repeated cycles every 3 weeks of entinostat (4 mg, 6 mg or 8 mg orally days 1 and 8) and clofarabine (10 mg/m2/day IV for 5 days, days 3-7) (Arm A). Adults aged 40-59 years with ND ALL/ABL or age ≥21 years in first relapse received entinostat and clofarabine prior to traditional chemotherapy on day 11 (Arm B). Changes in DNA damage, global protein lysine acetylation, myeloid-derived suppressor cells and monocytes were measured in PBMCs before and during therapy. RESULTS Twenty-eight patients were treated at three entinostat dose levels with the maximum administered dose being entinostat 8 mg. The regimen was well tolerated with infectious and metabolic derangements more common in the older population versus the younger cohort. There was no severe hyperglycemia and no peripheral neuropathy in this small study. There were 2 deaths (1 sepsis, 1 intracranial bleed). Overall response rate was 32 %; it was 50 % for ND ALL/ABL. Entinostat increased global protein acetylation and inhibited immunosuppressive monocyte subpopulations, while clofarabine induced DNA damage in all cell subsets examined. CONCLUSION Entinostat plus clofarabine appears to be tolerable and active in older adults with ND ALL/ABL, but less active in R/R patients. Further evaluation of this regimen in ND ALL/ABL appears warranted.
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Affiliation(s)
- Hetty E Carraway
- Hematology Oncology Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States.
| | - Yazeed Sawalha
- Arthur G. James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Ivana Gojo
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, United States
| | - Min-Jung Lee
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| | - Sunmin Lee
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| | - Yusuke Tomita
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| | - Akira Yuno
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| | - Jackie Greer
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, United States
| | - B Douglas Smith
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, United States
| | - Keith W Pratz
- The University of Pennsylvania, Philadelphia, Pennsylvania
| | - Mark J Levis
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, United States
| | - Steven D Gore
- Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, NIH, Bethesda, MD, United States
| | - Nilanjan Ghosh
- Atrium Health, Carolinas HealthCare System, Charlotte, NC, United States
| | - Amy Dezern
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, United States
| | - Amanda L Blackford
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, United States
| | - Maria R Baer
- University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States
| | - Lia Gore
- University of Colorado Cancer Center, Aurora, CO, United States
| | - Richard Piekarz
- Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, NIH, Bethesda, MD, United States
| | - Jane B Trepel
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| | - Judith E Karp
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, United States
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48
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Bauer I, Graessle S. Fungal Lysine Deacetylases in Virulence, Resistance, and Production of Small Bioactive Compounds. Genes (Basel) 2021; 12:1470. [PMID: 34680865 PMCID: PMC8535771 DOI: 10.3390/genes12101470] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 09/20/2021] [Indexed: 12/13/2022] Open
Abstract
The growing number of immunocompromised patients begs for efficient therapy strategies against invasive fungal infections. As conventional antifungal treatment is increasingly hampered by resistance to commonly used antifungals, development of novel therapy regimens is required. On the other hand, numerous fungal species are industrially exploited as cell factories of enzymes and chemicals or as producers of medically relevant pharmaceuticals. Consequently, there is immense interest in tapping the almost inexhaustible fungal portfolio of natural products for potential medical and industrial applications. Both the pathogenicity and production of those small metabolites are significantly dependent on the acetylation status of distinct regulatory proteins. Thus, classical lysine deacetylases (KDACs) are crucial virulence determinants and important regulators of natural products of fungi. In this review, we present an overview of the members of classical KDACs and their complexes in filamentous fungi. Further, we discuss the impact of the genetic manipulation of KDACs on the pathogenicity and production of bioactive molecules. Special consideration is given to inhibitors of these enzymes and their role as potential new antifungals and emerging tools for the discovery of novel pharmaceutical drugs and antibiotics in fungal producer strains.
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Affiliation(s)
| | - Stefan Graessle
- Institute of Molecular Biology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria;
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Kopczynski M, Rumienczyk I, Kulecka M, Statkiewicz M, Pysniak K, Sandowska-Markiewicz Z, Wojcik-Trechcinska U, Goryca K, Pyziak K, Majewska E, Masiejczyk M, Wojcik-Jaszczynska K, Rzymski T, Bomsztyk K, Ostrowski J, Mikula M. Selective Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibition by the SCH772984 Compound Attenuates In Vitro and In Vivo Inflammatory Responses and Prolongs Survival in Murine Sepsis Models. Int J Mol Sci 2021; 22:10204. [PMID: 34638546 PMCID: PMC8508766 DOI: 10.3390/ijms221910204] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/20/2021] [Accepted: 09/20/2021] [Indexed: 12/29/2022] Open
Abstract
Sepsis is the leading cause of death in intensive care units worldwide. Current treatments of sepsis are largely supportive and clinical trials using specific pharmacotherapy for sepsis have failed to improve outcomes. Here, we used the lipopolysaccharide (LPS)-stimulated mouse RAW264.7 cell line and AlphaLisa assay for TNFa as a readout to perform a supervised drug repurposing screen for sepsis treatment with compounds targeting epigenetic enzymes, including kinases. We identified the SCH772984 compound, an extracellular signal-regulated kinase (ERK) 1/2 inhibitor, as an effective blocker of TNFa production in vitro. RNA-Seq of the SCH772984-treated RAW264.7 cells at 1, 4, and 24 h time points of LPS challenge followed by functional annotation of differentially expressed genes highlighted the suppression of cellular pathways related to the immune system. SCH772984 treatment improved survival in the LPS-induced lethal endotoxemia and cecal ligation and puncture (CLP) mouse models of sepsis, and reduced plasma levels of Ccl2/Mcp1. Functional analyses of RNA-seq datasets for kidney, lung, liver, and heart tissues from SCH772984-treated animals collected at 6 h and 12 h post-CLP revealed a significant downregulation of pathways related to the immune response and platelets activation but upregulation of the extracellular matrix organization and retinoic acid signaling pathways. Thus, this study defined transcriptome signatures of SCH772984 action in vitro and in vivo, an agent that has the potential to improve sepsis outcome.
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Affiliation(s)
- Michal Kopczynski
- Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (M.K.); (I.R.); (M.K.); (M.S.); (K.P.); (Z.S.-M.); (U.W.-T.); (J.O.)
| | - Izabela Rumienczyk
- Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (M.K.); (I.R.); (M.K.); (M.S.); (K.P.); (Z.S.-M.); (U.W.-T.); (J.O.)
| | - Maria Kulecka
- Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (M.K.); (I.R.); (M.K.); (M.S.); (K.P.); (Z.S.-M.); (U.W.-T.); (J.O.)
- Department of Gastroenterology, Hepatology and Clinical Oncology, Centre for Postgraduate Medical Education, 01-813 Warsaw, Poland
| | - Małgorzata Statkiewicz
- Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (M.K.); (I.R.); (M.K.); (M.S.); (K.P.); (Z.S.-M.); (U.W.-T.); (J.O.)
| | - Kazimiera Pysniak
- Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (M.K.); (I.R.); (M.K.); (M.S.); (K.P.); (Z.S.-M.); (U.W.-T.); (J.O.)
| | - Zuzanna Sandowska-Markiewicz
- Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (M.K.); (I.R.); (M.K.); (M.S.); (K.P.); (Z.S.-M.); (U.W.-T.); (J.O.)
| | - Urszula Wojcik-Trechcinska
- Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (M.K.); (I.R.); (M.K.); (M.S.); (K.P.); (Z.S.-M.); (U.W.-T.); (J.O.)
| | - Krzysztof Goryca
- Genomics Core Facility, Centre of New Technologies, University of Warsaw, 02-097 Warsaw, Poland;
| | - Karolina Pyziak
- Biology R&D, Ryvu Therapeutics S.A., 30-394 Krakow, Poland; (K.P.); (E.M.); (M.M.); (K.W.-J.); (T.R.)
| | - Eliza Majewska
- Biology R&D, Ryvu Therapeutics S.A., 30-394 Krakow, Poland; (K.P.); (E.M.); (M.M.); (K.W.-J.); (T.R.)
| | - Magdalena Masiejczyk
- Biology R&D, Ryvu Therapeutics S.A., 30-394 Krakow, Poland; (K.P.); (E.M.); (M.M.); (K.W.-J.); (T.R.)
| | | | - Tomasz Rzymski
- Biology R&D, Ryvu Therapeutics S.A., 30-394 Krakow, Poland; (K.P.); (E.M.); (M.M.); (K.W.-J.); (T.R.)
| | - Karol Bomsztyk
- UW Medicine South Lake Union, University of Washington, Seattle, WA 98109, USA;
| | - Jerzy Ostrowski
- Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (M.K.); (I.R.); (M.K.); (M.S.); (K.P.); (Z.S.-M.); (U.W.-T.); (J.O.)
- Department of Gastroenterology, Hepatology and Clinical Oncology, Centre for Postgraduate Medical Education, 01-813 Warsaw, Poland
| | - Michal Mikula
- Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (M.K.); (I.R.); (M.K.); (M.S.); (K.P.); (Z.S.-M.); (U.W.-T.); (J.O.)
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Al-Hamashi AA, Koranne R, Dlamini S, Alqahtani A, Karaj E, Rashid MS, Knoff JR, Dunworth M, Pflum MKH, Casero RA, Perera L, Taylor WR, Tillekeratne LMV. A new class of cytotoxic agents targets tubulin and disrupts microtubule dynamics. Bioorg Chem 2021; 116:105297. [PMID: 34509798 PMCID: PMC8530978 DOI: 10.1016/j.bioorg.2021.105297] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/03/2021] [Accepted: 08/17/2021] [Indexed: 01/08/2023]
Abstract
Despite the advances in treatment strategies, cancer is still the second leading cause of death in the USA. A majority of the currently used cancer drugs have limitations in their clinical use due to poor selectivity, toxic side effects and multiple drug resistance, warranting the development of new anticancer drugs of different mechanisms of action. Here we describe the design, synthesis and initial biological evaluation of a new class of antimitotic agents that modulate tubulin polymerization. Structurally, these compounds are chalcone mimics containing a 1-(1H-imidazol-2-yl)ethan-1-one moiety, which was initially introduced to act as a metal-binding group and inhibit histone deacetylase enzymes. Although several analogues selectively inhibited purified HDAC8 with IC50 values in low micromolar range, tissue culture studies suggest that HDAC inhibition is not a major mechanism responsible for cytotoxicity. The compounds demonstrated cell growth inhibition with GI50 values of upper nanomolar to low micromolar potency with significant selectively for cancer over normal cells. Interestingly, several compounds arrested HeLaM cells in mitosis and seem to target tubulin to cause mitotic arrest. For example, when combined with inhibitors of Aurora B kinase, they led to dramatic disassembly of the mitotic spindle. In-vitro tubulin polymerization studies showed that the compounds reduced the rate of polymerization of microtubules during the elongation phase and lowered the amount of polymerized tubulin during the plateau phase. Finally, in silico docking studies identified binding of IPE-7 to the colchicine site with similar affinity as the test compound D64131. These compounds represent a new antimitotic pharmacophore with limited HDAC inhibitory activity.
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Affiliation(s)
- Ayad A Al-Hamashi
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH-43606, USA
| | - Radhika Koranne
- Department of Biological Sciences, College of Natural Sciences and Mathematics, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH-43606, USA
| | - Samkeliso Dlamini
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH-43606, USA
| | - Abdulateef Alqahtani
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH-43606, USA
| | - Endri Karaj
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH-43606, USA
| | - Maisha S Rashid
- Department of Biological Sciences, College of Natural Sciences and Mathematics, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH-43606, USA
| | - Joseph R Knoff
- Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, USA
| | - Matthew Dunworth
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Bunting/Blaustein Cancer Research Building 1 1650 Orleans Street - Room 551, Baltimore, MD 21231, USA
| | - Mary Kay H Pflum
- Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, USA
| | - Robert A Casero
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Bunting/Blaustein Cancer Research Building 1 1650 Orleans Street - Room 551, Baltimore, MD 21231, USA
| | - Lalith Perera
- Laboratory of Genome Integrity and Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA
| | - William R Taylor
- Department of Biological Sciences, College of Natural Sciences and Mathematics, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH-43606, USA.
| | - L M Viranga Tillekeratne
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, 2801, W. Bancroft Street, Toledo, OH-43606, USA.
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