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Delrieu L, Hamaidia S, Montaut E, Garcia-Sandoval AC, Teste C, Betton-Fraisse P, Bonnefoix T, Carras S, Gressin R, Lefebvre C, Govin J, Emadali A. BET inhibition revealed varying MYC dependency mechanisms independent of gene alterations in aggressive B-cell lymphomas. Clin Epigenetics 2024; 16:185. [PMID: 39702340 DOI: 10.1186/s13148-024-01788-7] [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: 06/27/2024] [Accepted: 11/19/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND MYC-driven lymphomas are a subset of B-cell lymphomas characterized by genetic alterations that dysregulate the expression of the MYC oncogene. When overexpressed, typically through chromosomal translocations, amplifications, or other mechanisms, MYC can drive uncontrolled cell growth and contribute to cancer development. MYC-driven lymphomas are described as aggressive entities which require intensive treatment approaches and can be associated with poor prognosis. In the absence of direct MYC-targeting therapy, epigenetic drugs called BET inhibitors (BETi) were shown to reduce MYC levels by disrupting BRD4-dependent transcription associated with the expression of MYC, as well as other oncogenes. Here, we used BETi as molecular tools to better understand oncogenic dependencies in a panel of cell line models of MYC-driven B-cell lymphoma selected to represent their genetic heterogeneity. RESULTS We first showed that, in these models, MYC expression level does not strictly correlate to the presence of gene alterations. Our data also demonstrated that BETi induces similar growth arrest in all lymphoma cell lines independently of MYC mutational status or expression level. In contrast, BETi-induced cell death was only observed in two cell lines presenting the highest level of MYC protein. This suggests that some MYC-driven lymphoma could present a stronger dependency on MYC for their survival which cannot be predicted on the sole basis on their genetics. This hypothesis was confirmed by gene invalidation experiments, which showed that MYC loss recapitulates the effect of BETi treatment on both cell proliferation and survival, confirming MYC oncogene dependency in models sensitive to BETi cytotoxicity. In contrast, the growth arrest observed in cell lines resistant to BETi-induced apoptosis is not mediated through MYC, but rather through alternative pro-proliferative or oncogenic pathways. Gene expression profiling revealed the basal activation of a specific non-canonical WNT/Hippo pathway in cell death-resistant cell lines that could be targeted in combination therapy to restore BETi cytotoxicity. CONCLUSION This work brings new insights into the complexity of MYC-dependencies and unravels a novel targetable oncogenic pathway in aggressive B-cell lymphomas.
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Affiliation(s)
- Loris Delrieu
- Univ. Grenoble Alpes, Inserm, CNRS, Institute for Advanced Biosciences, Grenoble, France
| | - Sieme Hamaidia
- Univ. Grenoble Alpes, Inserm, CNRS, Institute for Advanced Biosciences, Grenoble, France
- Recherche and Innovation Unit, Grenoble Alpes University Hospital, Grenoble, France
| | - Emilie Montaut
- Univ. Grenoble Alpes, Inserm, CNRS, Institute for Advanced Biosciences, Grenoble, France
- Recherche and Innovation Unit, Grenoble Alpes University Hospital, Grenoble, France
| | | | - Camille Teste
- Univ. Grenoble Alpes, Inserm, CNRS, Institute for Advanced Biosciences, Grenoble, France
| | | | - Thierry Bonnefoix
- Univ. Grenoble Alpes, Inserm, CNRS, Institute for Advanced Biosciences, Grenoble, France
- Recherche and Innovation Unit, Grenoble Alpes University Hospital, Grenoble, France
| | - Sylvain Carras
- Univ. Grenoble Alpes, Inserm, CNRS, Institute for Advanced Biosciences, Grenoble, France
- Hematology, Oncogenetics and Immunology Unit, Grenoble Alpes University Hospital, Grenoble, France
- Department of Clinical Hematology, Grenoble Alpes University Hospital, Grenoble, France
| | - Rémy Gressin
- Univ. Grenoble Alpes, Inserm, CNRS, Institute for Advanced Biosciences, Grenoble, France
- Department of Clinical Hematology, Grenoble Alpes University Hospital, Grenoble, France
| | - Christine Lefebvre
- Univ. Grenoble Alpes, Inserm, CNRS, Institute for Advanced Biosciences, Grenoble, France
- Hematology, Oncogenetics and Immunology Unit, Grenoble Alpes University Hospital, Grenoble, France
| | - Jérôme Govin
- Univ. Grenoble Alpes, Inserm, CNRS, Institute for Advanced Biosciences, Grenoble, France
| | - Anouk Emadali
- Univ. Grenoble Alpes, Inserm, CNRS, Institute for Advanced Biosciences, Grenoble, France.
- Recherche and Innovation Unit, Grenoble Alpes University Hospital, Grenoble, France.
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He Q, Hu J, Huang H, Wu T, Li W, Ramakrishnan S, Pan Y, Chan KM, Zhang L, Yang M, Wang X, Chin YR. FOSL1 is a key regulator of a super-enhancer driving TCOF1 expression in triple-negative breast cancer. Epigenetics Chromatin 2024; 17:34. [PMID: 39523372 PMCID: PMC11552368 DOI: 10.1186/s13072-024-00559-1] [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] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 11/03/2024] [Indexed: 11/16/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with an unmet clinical need, but its epigenetic regulation remains largely undefined. By performing multiomic profiling, we recently revealed distinct super-enhancer (SE) patterns in different subtypes of breast cancer and identified a number of TNBC-specific SEs that drive oncogene expression. One of these SEs, TCOF1 SE, was discovered to play an important oncogenic role in TNBC. However, the molecular mechanisms by which TCOF1 SE promotes the expression of the TCOF1 gene remain to be elucidated. Here, by using combinatorial approaches of DNA pull-down assay, bioinformatics analysis and functional studies, we identified FOSL1 as a key transcription factor that binds to TCOF1 SE and drives its overexpression. shRNA-mediated depletion of FOSL1 results in significant downregulation of TCOF1 mRNA and protein levels. Using a dual-luciferase reporter assay and ChIP-qPCR, we showed that binding of FOSL1 to TCOF1 SE promotes the transcription of TCOF1 in TNBC cells. Importantly, our data demonstrated that overexpression of FOSL1 drives the activation of TCOF1 SE. Lastly, depletion of FOSL1 inhibits tumor spheroid growth and stemness properties of TNBC cells. Taken together, these findings uncover the key epigenetic role of FOSL1 and highlight the potential of targeting the FOSL1-TCOF1 axis for TNBC treatment.
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Affiliation(s)
- Qingling He
- Tung Biomedical Sciences Centre, Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Jianyang Hu
- Tung Biomedical Sciences Centre, Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
- City University of Hong Kong Shenzhen Research Institute, Shenzhen, China
| | - Hao Huang
- Tung Biomedical Sciences Centre, Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Tan Wu
- Tung Biomedical Sciences Centre, Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Wenxiu Li
- Tung Biomedical Sciences Centre, Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Saravanan Ramakrishnan
- Tung Biomedical Sciences Centre, Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Yilin Pan
- Tung Biomedical Sciences Centre, Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Kui Ming Chan
- Tung Biomedical Sciences Centre, Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
- City University of Hong Kong Shenzhen Research Institute, Shenzhen, China
| | - Liang Zhang
- Tung Biomedical Sciences Centre, Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
- City University of Hong Kong Shenzhen Research Institute, Shenzhen, China
| | - Mengsu Yang
- Tung Biomedical Sciences Centre, Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
- City University of Hong Kong Shenzhen Research Institute, Shenzhen, China
| | - Xin Wang
- Department of Surgery, The Chinese University of Hong Kong, New Territories, Hong Kong, China
| | - Y Rebecca Chin
- Tung Biomedical Sciences Centre, Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China.
- City University of Hong Kong Shenzhen Research Institute, Shenzhen, China.
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Morii M, Kubota S, Iimori M, Yokomizo-Nakano T, Hamashima A, Bai J, Nishimura A, Tasaki M, Ando Y, Araki K, Sashida G. TIF1β activates leukemic transcriptional program in HSCs and promotes BCR::ABL1-induced myeloid leukemia. Leukemia 2024; 38:1275-1286. [PMID: 38734786 DOI: 10.1038/s41375-024-02276-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 04/26/2024] [Accepted: 05/01/2024] [Indexed: 05/13/2024]
Abstract
TIF1β/KAP1/TRIM28, a chromatin modulator, both represses and activates the transcription of genes in normal and malignant cells. Analyses of datasets on leukemia patients revealed that the expression level of TIF1β was increased in patients with chronic myeloid leukemia at the blast crisis and acute myeloid leukemia. We generated a BCR::ABL1 conditional knock-in (KI) mouse model, which developed aggressive myeloid leukemia, and demonstrated that the deletion of the Tif1β gene inhibited the progression of myeloid leukemia and showed longer survival than that in BCR::ABL1 KI mice, suggesting that Tif1β drove the progression of BCR::ABL1-induced leukemia. In addition, the deletion of Tif1β sensitized BCR::ABL1 KI leukemic cells to dasatinib. The deletion of Tif1β decreased the expression levels of TIF1β-target genes and chromatin accessibility peaks enriched with the Fosl1-binding motif in BCR::ABL1 KI stem cells. TIF1β directly bound to the promoters of proliferation genes, such as FOSL1, in human BCR::ABL1 cells, in which TIF1β and FOSL1 bound to adjacent regions of chromatin. Since the expression of Fosl1 was critical for the enhanced growth of BCR::ABL1 KI cells, Tif1β and Fosl1 interacted to activate the leukemic transcriptional program in and cellular function of BCR::ABL1 KI stem cells and drove the progression of myeloid leukemia.
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MESH Headings
- Animals
- Humans
- Mice
- Fusion Proteins, bcr-abl/genetics
- Fusion Proteins, bcr-abl/metabolism
- Gene Expression Regulation, Leukemic
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Transcription, Genetic
- Tripartite Motif-Containing Protein 28/metabolism
- Tripartite Motif-Containing Protein 28/genetics
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Affiliation(s)
- Mariko Morii
- Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Sho Kubota
- Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Mihoko Iimori
- Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Takako Yokomizo-Nakano
- Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Ai Hamashima
- Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Jie Bai
- Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Akiho Nishimura
- Gastrointestinal Cancer Biology, International Research Center of Medical Sciences, Kumamoto University, Kumamoto, 860-0811, Japan
| | - Masayoshi Tasaki
- Department of Biomedical Laboratory Sciences, Graduate School of Health Sciences, Kumamoto University, Kumamoto, Japan
| | - Yukio Ando
- Department of Amyloidosis Research, Nagasaki International University, Sasebo, Japan
| | - Kimi Araki
- Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan
- Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, Japan
| | - Goro Sashida
- Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
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4
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Rout AK, Dehury B, Parida SN, Rout SS, Jena R, Kaushik N, Kaushik NK, Pradhan SK, Sahoo CR, Singh AK, Arya M, Behera BK. A review on structure-function mechanism and signaling pathway of serine/threonine protein PIM kinases as a therapeutic target. Int J Biol Macromol 2024; 270:132030. [PMID: 38704069 DOI: 10.1016/j.ijbiomac.2024.132030] [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: 11/24/2023] [Revised: 04/05/2024] [Accepted: 04/30/2024] [Indexed: 05/06/2024]
Abstract
The proviral integration for the Moloney murine leukemia virus (PIM) kinases, belonging to serine/threonine kinase family, have been found to be overexpressed in various types of cancers, such as prostate, breast, colon, endometrial, gastric, and pancreatic cancer. The three isoforms PIM kinases i.e., PIM1, PIM2, and PIM3 share a high degree of sequence and structural similarity and phosphorylate substrates controlling tumorigenic phenotypes like proliferation and cell survival. Targeting short-lived PIM kinases presents an intriguing strategy as in vivo knock-down studies result in non-lethal phenotypes, indicating that clinical inhibition of PIM might have fewer adverse effects. The ATP binding site (hinge region) possesses distinctive attributes, which led to the development of novel small molecule scaffolds that target either one or all three PIM isoforms. Machine learning and structure-based approaches have been at the forefront of developing novel and effective chemical therapeutics against PIM in preclinical and clinical settings, and none have yet received approval for cancer treatment. The stability of PIM isoforms is maintained by PIM kinase activity, which leads to resistance against PIM inhibitors and chemotherapy; thus, to overcome such effects, PIM proteolysis targeting chimeras (PROTACs) are now being developed that specifically degrade PIM proteins. In this review, we recapitulate an overview of the oncogenic functions of PIM kinases, their structure, function, and crucial signaling network in different types of cancer, and the potential of pharmacological small-molecule inhibitors. Further, our comprehensive review also provides valuable insights for developing novel antitumor drugs that specifically target PIM kinases in the future. In conclusion, we provide insights into the benefits of degrading PIM kinases as opposed to blocking their catalytic activity to address the oncogenic potential of PIM kinases.
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Affiliation(s)
- Ajaya Kumar Rout
- Rani Lakshmi Bai Central Agricultural University, Jhansi-284003, Uttar Pradesh, India
| | - Budheswar Dehury
- Department of Bioinformatics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal-576104, India
| | - Satya Narayan Parida
- Rani Lakshmi Bai Central Agricultural University, Jhansi-284003, Uttar Pradesh, India
| | - Sushree Swati Rout
- Department of Zoology, Fakir Mohan University, Balasore-756089, Odisha, India
| | - Rajkumar Jena
- Department of Zoology, Fakir Mohan University, Balasore-756089, Odisha, India
| | - Neha Kaushik
- Department of Biotechnology, The University of Suwon, Hwaseong si, South Korea
| | | | - Sukanta Kumar Pradhan
- Department of Bioinformatics, Odisha University of Agriculture and Technology, Bhubaneswar-751003, Odisha, India
| | - Chita Ranjan Sahoo
- ICMR-Regional Medical Research Centre, Department of Health Research, Ministry of Health and Family Welfare, Government of India, Bhubaneswar-751023, India
| | - Ashok Kumar Singh
- Rani Lakshmi Bai Central Agricultural University, Jhansi-284003, Uttar Pradesh, India
| | - Meenakshi Arya
- Rani Lakshmi Bai Central Agricultural University, Jhansi-284003, Uttar Pradesh, India.
| | - Bijay Kumar Behera
- Rani Lakshmi Bai Central Agricultural University, Jhansi-284003, Uttar Pradesh, India.
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5
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Chatterjee S, Prashanth P, Rawat V, Ghosh Roy S. Regulation of lipid and serine metabolism by the oncogene c-Myc. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 389:236-256. [PMID: 39396848 DOI: 10.1016/bs.ircmb.2024.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Tumor formation is supported by metabolic reprogramming, characterized by increase nutrient uptake, glycolysis and glutaminolysis. The c-Myc proto-oncogene is a transcription factor, upregulated in most cancers and several reports showed the role of c-Myc in other metabolic pathways such as glucose, amino acid, and nucleotide metabolism. In this short report, we tried to summarize the existing takeaway points from studies conducted in different cancer types with respect to c-Myc and lipid and serine metabolism. Here, we report that c-Myc can activate both lipid and serine metabolism against the backdrop of tumor formation, and different therapies like aspirin and lomitapide target the links between c-Myc and metabolism to slow down tumor progression and invasion. We also report diverse upstream regulators that influence c-Myc in different cancers, and interestingly components of the lipid metabolism (like lipid phosphate phosphatase and leptin) and serine metabolism can also act upstream of c-Myc in certain occasions. Finally, we also summarize the existing knowledge on the involvement of epigenetic pathways and non-coding RNAs in regulating lipid and serine metabolism and c-Myc in tumor cells. Identification of non-coding factors and epigenetic mechanisms present a promising avenue of study that could empower researchers with novel anticancer treatment targeting c-Myc and lipid and serine metabolism pathways!
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Affiliation(s)
- Subhajit Chatterjee
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Prarthana Prashanth
- Department of Physiology and Biophysics, University of Illinois College of Medicine, University of Illinois Cancer Center, Chicago, IL, United States
| | - Vipin Rawat
- Department of Physiology and Biophysics, University of Illinois College of Medicine, University of Illinois Cancer Center, Chicago, IL, United States.
| | - Sounak Ghosh Roy
- Henry M Jackson Foundation for the Advancement of Military Medicine (In Support of Agile Vaccines & Therapeutics, Directorate for Defense Infectious Diseases Research, Naval Medical Research Command, Silver Spring, MD, United States.
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6
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Chen L, Mao W, Ren C, Li J, Zhang J. Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles. J Med Chem 2024; 67:38-64. [PMID: 38164076 DOI: 10.1021/acs.jmedchem.3c01802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
Proviral integration sitea for Moloney-murine leukemia virus (PIM) kinases are a family of highly conserved serine/tyrosine kinases consisting of three members, PIM-1, PIM-2, and PIM-3. These kinases regulate a wide range of substrates through phosphorylation and affect key cellular processes such as transcription, translation, proliferation, apoptosis, and energy metabolism. Several PIM inhibitors are currently undergoing clinical trials, such as a phase I clinical trial of Uzanserti (5) for the treatment of relapsed diffuse large B-cell lymphoma that has been completed. The current focus encompasses the structural and biological characterization of PIM, ongoing research progress on small-molecule inhibitors undergoing clinical trials, and evaluation analysis of persisting challenges in this field. Additionally, the design and discovery of small-molecule inhibitors targeting PIM in recent years have been explored, with a particular emphasis on medicinal chemistry, aiming to provide valuable insights for the future development of PIM inhibitors.
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Affiliation(s)
- Li Chen
- Department of Neurology, Joint Research Institution of Altitude Health and Institute of Respiratory Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China
| | - Wuyu Mao
- Department of Neurology, Joint Research Institution of Altitude Health and Institute of Respiratory Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Changyu Ren
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu 611130, Sichuan, China
| | - Jinqi Li
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China
| | - Jifa Zhang
- Department of Neurology, Joint Research Institution of Altitude Health and Institute of Respiratory Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
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7
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Davarinejad H, Arvanitis-Vigneault A, Nygard D, Lavallée-Adam M, Couture JF. Modus operandi: Chromatin recognition by α-helical histone readers. Structure 2024; 32:8-17. [PMID: 37922903 DOI: 10.1016/j.str.2023.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/25/2023] [Accepted: 10/10/2023] [Indexed: 11/07/2023]
Abstract
Histone reader domains provide a mechanism for sensing states of coordinated nuclear processes marked by histone proteins' post-translational modifications (PTMs). Among a growing number of discovered histone readers, the 14-3-3s, ankyrin repeat domains (ARDs), tetratricopeptide repeats (TPRs), bromodomains (BRDs), and HEAT domains are a group of domains using various mechanisms to recognize unmodified or modified histones, yet they all are composed of an α-helical fold. In this review, we compare how these readers fold to create protein domains that are very diverse in their tertiary structures, giving rise to intriguing peptide binding mechanisms resulting in vastly different footprints of their targets.
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Affiliation(s)
- Hossein Davarinejad
- Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Alexis Arvanitis-Vigneault
- Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Dallas Nygard
- Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Mathieu Lavallée-Adam
- Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Jean-François Couture
- Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
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8
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Karati D, Saha A, Roy S, Mukherjee S. PIM Kinase Inhibitors as Novel Promising Therapeutic Scaffolds in Cancer Therapy. Curr Top Med Chem 2024; 24:2489-2508. [PMID: 39297470 DOI: 10.2174/0115680266321659240906114742] [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: 04/06/2024] [Revised: 08/24/2024] [Accepted: 08/28/2024] [Indexed: 11/21/2024]
Abstract
Cancer involves the uncontrolled, abnormal growth of cells and affects other tissues. Kinase has an impact on proliferating the cells and causing cancer. For the purpose of treating cancer, PIM kinase is a potential target. The pro-viral Integration site for moloney murine leukaemia virus (PIM) kinases is responsible for the tumorigenesis, by phosphorylating the proteins that control the cell cycle and cell proliferation. PIM-1, PIM-2, and PIM-3 are the three distinct isoforms of PIM kinases. The JAK/STAT pathway is essential for controlling how PIM genes are expressed. PIM kinase is also linked withPI3K/AKT/mTOR pathway in various types of cancers. The overexpression of PIM kinase will cause cancer. Currently, there are significant efforts being made in medication design and development to target its inhibition. A few small chemical inhibitors (E.g., SGI-1776, AZD1208, LGH447) that specifically target the PIM proteins' adenosine triphosphate (ATP)-binding domain have been identified. PIM kinase antagonists have a remarkable effect on different types of cancer. Despite conducting clinical trials on SGI-1776, the first PIM inhibitory agent, was prematurely withdrawn, making it unable to generate concept evidence. On the other hand, in recent years, it has aided in hastening the identification of multiple new PIM inhibitors. Cyanopyridines and Pyrazolo[1,5-a]pyrimidinecan act as potent PIM kinase inhibitors for cancer therapy. We explore the involvement of oncogenic transcription factor c-Mycandmi-RNA in relation to PIM kinase. In this article, we highlight the oncogenic effects, and structural insights into PIM kinase inhibitors for the treatment of cancer.
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Affiliation(s)
- Dipanjan Karati
- Department of Pharmaceutical Technology, School of Pharmacy, Techno India University, Kolkata 700091, West Bengal, India
| | - Ankur Saha
- Department of Pharmaceutical Technology, School of Pharmacy, Techno India University, Kolkata 700091, West Bengal, India
| | - Souvik Roy
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata - Group of Institutions, 124, B.L Saha Road, Kolkata 700053, West Bengal, India
| | - Swarupananda Mukherjee
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata - Group of Institutions, 124, B.L Saha Road, Kolkata 700053, West Bengal, India
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9
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Ingle K, LaComb JF, Graves LM, Baines AT, Bialkowska AB. AUM302, a novel triple kinase PIM/PI3K/mTOR inhibitor, is a potent in vitro pancreatic cancer growth inhibitor. PLoS One 2023; 18:e0294065. [PMID: 37943821 PMCID: PMC10635512 DOI: 10.1371/journal.pone.0294065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 10/24/2023] [Indexed: 11/12/2023] Open
Abstract
Pancreatic cancer is one of the leading causes of cancer deaths, with pancreatic ductal adenocarcinoma (PDAC) being the most common subtype. Advanced stage diagnosis of PDAC is common, causing limited treatment opportunities. Gemcitabine is a frequently used chemotherapeutic agent which can be used as a monotherapy or in combination. However, tumors often develop resistance to gemcitabine. Previous studies show that the proto-oncogene PIM kinases (PIM1 and PIM3) are upregulated in PDAC compared to matched normal tissue and are related to chemoresistance and PDAC cell growth. The PIM kinases are also involved in the PI3K/AKT/mTOR pathway to promote cell survival. In this study, we evaluate the effect of the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, and commercially available PIM inhibitor, TP-3654. Using five human PDAC cell lines, we found AUM302 to be a potent inhibitor of cell proliferation, cell viability, cell cycle progression, and phosphoprotein expression, while TP-3654 was less effective. Significantly, AUM302 had a strong impact on the viability of gemcitabine-resistant PDAC cells. Taken together, these results demonstrate that AUM302 exhibits antitumor activity in human PDAC cells and thus has the potential to be an effective drug for PDAC therapy.
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Affiliation(s)
- Komala Ingle
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, New York, United States of America
| | - Joseph F. LaComb
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, New York, United States of America
| | - Lee M. Graves
- Department of Pharmacology, School of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Antonio T. Baines
- Department of Pharmacology, School of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Biological & Biomedical Sciences, College of Health & Sciences, North Carolina Central University, Durham, North Carolina, United States of America
| | - Agnieszka B. Bialkowska
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, New York, United States of America
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10
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Kotekar A, Singh AK, Devaiah BN. BRD4 and MYC: power couple in transcription and disease. FEBS J 2023; 290:4820-4842. [PMID: 35866356 PMCID: PMC9867786 DOI: 10.1111/febs.16580] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/16/2022] [Accepted: 07/20/2022] [Indexed: 01/26/2023]
Abstract
The MYC proto-oncogene and BRD4, a BET family protein, are two cardinal proteins that have a broad influence in cell biology and disease. Both proteins are expressed ubiquitously in mammalian cells and play central roles in controlling growth, development, stress responses and metabolic function. As chromatin and transcriptional regulators, they play a critical role in regulating the expression of a burgeoning array of genes, maintaining chromatin architecture and genome stability. Consequently, impairment of their function or regulation leads to many diseases, with cancer being the most predominant. Interestingly, accumulating evidence indicates that regulation of the expression and functions of MYC are tightly intertwined with BRD4 at both transcriptional and post-transcriptional levels. Here, we review the mechanisms by which MYC and BRD4 are regulated, their functions in governing various molecular mechanisms and the consequences of their dysregulation that lead to disease. We present a perspective of how the regulatory mechanisms for the two proteins could be entwined at multiple points in a BRD4-MYC nexus that leads to the modulation of their functions and disease upon dysregulation.
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Affiliation(s)
- Aparna Kotekar
- Experimental Immunology Branch, NCI, NIH, Bethesda, MD 20892, USA
| | - Amit Kumar Singh
- Experimental Immunology Branch, NCI, NIH, Bethesda, MD 20892, USA
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11
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Casalino L, Talotta F, Matino I, Verde P. FRA-1 as a Regulator of EMT and Metastasis in Breast Cancer. Int J Mol Sci 2023; 24:ijms24098307. [PMID: 37176013 PMCID: PMC10179602 DOI: 10.3390/ijms24098307] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/21/2023] [Accepted: 05/01/2023] [Indexed: 05/15/2023] Open
Abstract
Among FOS-related components of the dimeric AP-1 transcription factor, the oncoprotein FRA-1 (encoded by FOSL1) is a key regulator of invasion and metastasis. The well-established FRA-1 pro-invasive activity in breast cancer, in which FOSL1 is overexpressed in the TNBC (Triple Negative Breast Cancer)/basal subtypes, correlates with the FRA-1-dependent transcriptional regulation of EMT (Epithelial-to-Mesenchymal Transition). After summarizing the major findings on FRA-1 in breast cancer invasiveness, we discuss the FRA-1 mechanistic links with EMT and cancer cell stemness, mediated by transcriptional and posttranscriptional interactions between FOSL1/FRA-1 and EMT-regulating transcription factors, miRNAs, RNA binding proteins and cytokines, along with other target genes involved in EMT. In addition to the FRA-1/AP-1 effects on the architecture of target promoters, we discuss the diagnostic and prognostic significance of the EMT-related FRA-1 transcriptome, along with therapeutic implications. Finally, we consider several novel perspectives regarding the less explored roles of FRA-1 in the tumor microenvironment and in control of the recently characterized hybrid EMT correlated with cancer cell plasticity, stemness, and metastatic potential. We will also examine the application of emerging technologies, such as single-cell analyses, along with animal models of TNBC and tumor-derived CTCs and PDXs (Circulating Tumor Cells and Patient-Derived Xenografts) for studying the FRA-1-mediated mechanisms in in vivo systems of EMT and metastasis.
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Affiliation(s)
- Laura Casalino
- Institute of Genetics and Biophysics "A. Buzzati Traverso", Consiglio Nazionale delle Ricerche (CNR), Via Pietro Castellino, 111, 80131 Naples, Italy
| | - Francesco Talotta
- Institute of Genetics and Biophysics "A. Buzzati Traverso", Consiglio Nazionale delle Ricerche (CNR), Via Pietro Castellino, 111, 80131 Naples, Italy
| | - Ilenia Matino
- Institute of Genetics and Biophysics "A. Buzzati Traverso", Consiglio Nazionale delle Ricerche (CNR), Via Pietro Castellino, 111, 80131 Naples, Italy
| | - Pasquale Verde
- Institute of Genetics and Biophysics "A. Buzzati Traverso", Consiglio Nazionale delle Ricerche (CNR), Via Pietro Castellino, 111, 80131 Naples, Italy
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12
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Saeed H, Leibowitz BJ, Zhang L, Yu J. Targeting Myc-driven stress addiction in colorectal cancer. Drug Resist Updat 2023; 69:100963. [PMID: 37119690 DOI: 10.1016/j.drup.2023.100963] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 04/06/2023] [Accepted: 04/17/2023] [Indexed: 05/01/2023]
Abstract
MYC is a proto-oncogene that encodes a powerful regulator of transcription and cellular programs essential for normal development, as well as the growth and survival of various types of cancer cells. MYC rearrangement and amplification is a common cause of hematologic malignancies. In epithelial cancers such as colorectal cancer, genetic alterations in MYC are rare. Activation of Wnt, ERK/MAPK, and PI3K/mTOR pathways dramatically increases Myc levels through enhanced transcription, translation, and protein stability. Elevated Myc promotes stress adaptation, metabolic reprogramming, and immune evasion to drive cancer development and therapeutic resistance through broad changes in transcriptional and translational landscapes. Despite intense interest and effort, Myc remains a difficult drug target. Deregulation of Myc and its targets has profound effects that vary depending on the type of cancer and the context. Here, we summarize recent advances in the mechanistic understanding of Myc-driven oncogenesis centered around mRNA translation and proteostress. Promising strategies and agents under development to target Myc are also discussed with a focus on colorectal cancer.
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Affiliation(s)
- Haris Saeed
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, 5117 Centre Ave., Pittsburgh, PA 15213, USA; Dept. of Pathology, University of Pittsburgh School of Medicine, 5117 Centre Ave., Pittsburgh, PA 15213, USA
| | - Brian J Leibowitz
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, 5117 Centre Ave., Pittsburgh, PA 15213, USA; Dept. of Pathology, University of Pittsburgh School of Medicine, 5117 Centre Ave., Pittsburgh, PA 15213, USA
| | - Lin Zhang
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, 5117 Centre Ave., Pittsburgh, PA 15213, USA; Dept. of Chemical Biology and Pharmacology, University of Pittsburgh School of Medicine, 5117 Centre Ave., Pittsburgh, PA 15213, USA
| | - Jian Yu
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, 5117 Centre Ave., Pittsburgh, PA 15213, USA; Dept. of Pathology, University of Pittsburgh School of Medicine, 5117 Centre Ave., Pittsburgh, PA 15213, USA; Dept. of Radiation Oncology, University of Pittsburgh School of Medicine, 5117 Centre Ave., Pittsburgh, PA 15213, USA.
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13
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Boi D, Rubini E, Breccia S, Guarguaglini G, Paiardini A. When Just One Phosphate Is One Too Many: The Multifaceted Interplay between Myc and Kinases. Int J Mol Sci 2023; 24:4746. [PMID: 36902175 PMCID: PMC10003727 DOI: 10.3390/ijms24054746] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 02/19/2023] [Accepted: 02/21/2023] [Indexed: 03/06/2023] Open
Abstract
Myc transcription factors are key regulators of many cellular processes, with Myc target genes crucially implicated in the management of cell proliferation and stem pluripotency, energy metabolism, protein synthesis, angiogenesis, DNA damage response, and apoptosis. Given the wide involvement of Myc in cellular dynamics, it is not surprising that its overexpression is frequently associated with cancer. Noteworthy, in cancer cells where high Myc levels are maintained, the overexpression of Myc-associated kinases is often observed and required to foster tumour cells' proliferation. A mutual interplay exists between Myc and kinases: the latter, which are Myc transcriptional targets, phosphorylate Myc, allowing its transcriptional activity, highlighting a clear regulatory loop. At the protein level, Myc activity and turnover is also tightly regulated by kinases, with a finely tuned balance between translation and rapid protein degradation. In this perspective, we focus on the cross-regulation of Myc and its associated protein kinases underlying similar and redundant mechanisms of regulation at different levels, from transcriptional to post-translational events. Furthermore, a review of the indirect effects of known kinase inhibitors on Myc provides an opportunity to identify alternative and combined therapeutic approaches for cancer treatment.
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Affiliation(s)
- Dalila Boi
- Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Elisabetta Rubini
- Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Sara Breccia
- Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Giulia Guarguaglini
- Institute of Molecular Biology and Pathology, National Research Council of Italy, Sapienza University of Rome, 00185 Rome, Italy
| | - Alessandro Paiardini
- Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy
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14
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Karadkhelkar NM, Lin M, Eubanks LM, Janda KD. Demystifying the Druggability of the MYC Family of Oncogenes. J Am Chem Soc 2023; 145:3259-3269. [PMID: 36734615 PMCID: PMC10182829 DOI: 10.1021/jacs.2c12732] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The MYC family of oncogenes (MYC, MYCN, and MYCL) encodes a basic helix-loop-helix leucine zipper (bHLHLZ) transcriptional regulator that is responsible for moving the cell through the restriction point. Through the HLHZIP domain, MYC heterodimerizes with the bHLHLZ protein MAX, which enables this MYC-MAX complex to bind to E-box regulatory DNA elements thereby controlling transcription of a large group of genes and their proteins. Translationally, MYC is one of the foremost oncogenic targets, and deregulation of expression of the MYC family gene/proteins occurs in over half of all human tumors and is recognized as a hallmark of cancer initiation and maintenance. Additionally, unexpected roles for this oncoprotein have been found in cancers that nominally have a non-MYC etiology. Although MYC is rarely mutated, its gain of function in cancer results from overexpression or from amplification. Moreover, MYC is a pleiotropic transcription factor possessing broad pathogenic prominence making it a coveted cancer target. A widely held notion within the biomedical research community is that the reliable modulation of MYC represents a tremendous therapeutic opportunity given its role in directly potentiating oncogenesis. However, the MYC-MAX heterodimer interaction contains a large surface area with a lack of well-defined binding sites creating the perception that targeting of MYC-MAX is forbidding. Here, we discuss the biochemistry behind MYC and MYC-MAX as it relates to cancer progression associated with these transcription factors. We also discuss the notion that MYC should no longer be regarded as undruggable, providing examples that a therapeutic window is achievable despite global MYC inhibition.
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Affiliation(s)
- Nishant M. Karadkhelkar
- Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, La Jolla, California 92037, United States
| | - Mingliang Lin
- Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, La Jolla, California 92037, United States
| | - Lisa M. Eubanks
- Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, La Jolla, California 92037, United States
| | - Kim D. Janda
- Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, La Jolla, California 92037, United States
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15
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Targeting Pim kinases in hematological cancers: molecular and clinical review. Mol Cancer 2023; 22:18. [PMID: 36694243 PMCID: PMC9875428 DOI: 10.1186/s12943-023-01721-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 01/13/2023] [Indexed: 01/26/2023] Open
Abstract
Decades of research has recognized a solid role for Pim kinases in lymphoproliferative disorders. Often up-regulated following JAK/STAT and tyrosine kinase receptor signaling, Pim kinases regulate cell proliferation, survival, metabolism, cellular trafficking and signaling. Targeting Pim kinases represents an interesting approach since knock-down of Pim kinases leads to non-fatal phenotypes in vivo suggesting clinical inhibition of Pim may have less side effects. In addition, the ATP binding site offers unique characteristics that can be used for the development of small inhibitors targeting one or all Pim isoforms. This review takes a closer look at Pim kinase expression and involvement in hematopoietic cancers. Current and past clinical trials and in vitro characterization of Pim kinase inhibitors are examined and future directions are discussed. Current studies suggest that Pim kinase inhibition may be most valuable when accompanied by multi-drug targeting therapy.
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16
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Markouli M, Strepkos D, Piperi C. Impact of Histone Modifications and Their Therapeutic Targeting in Hematological Malignancies. Int J Mol Sci 2022; 23:13657. [PMID: 36362442 PMCID: PMC9654260 DOI: 10.3390/ijms232113657] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/31/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022] Open
Abstract
Hematologic malignancies are a large and heterogeneous group of neoplasms characterized by complex pathogenetic mechanisms. The abnormal regulation of epigenetic mechanisms and specifically, histone modifications, has been demonstrated to play a central role in hematological cancer pathogenesis and progression. A variety of epigenetic enzymes that affect the state of histones have been detected as deregulated, being either over- or underexpressed, which induces changes in chromatin compaction and, subsequently, affects gene expression. Recent advances in the field of epigenetics have revealed novel therapeutic targets, with many epigenetic drugs being investigated in clinical trials. The present review focuses on the biological impact of histone modifications in the pathogenesis of hematologic malignancies, describing a wide range of therapeutic agents that have been discovered to target these alterations and are currently under investigation in clinical trials.
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Affiliation(s)
| | | | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.M.); (D.S.)
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17
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Donati G, Amati B. MYC and therapy resistance in cancer: risks and opportunities. Mol Oncol 2022; 16:3828-3854. [PMID: 36214609 PMCID: PMC9627787 DOI: 10.1002/1878-0261.13319] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/08/2022] [Accepted: 10/06/2022] [Indexed: 12/24/2022] Open
Abstract
The MYC transcription factor, encoded by the c-MYC proto-oncogene, is activated by growth-promoting signals, and is a key regulator of biosynthetic and metabolic pathways driving cell growth and proliferation. These same processes are deregulated in MYC-driven tumors, where they become critical for cancer cell proliferation and survival. As other oncogenic insults, overexpressed MYC induces a series of cellular stresses (metabolic, oxidative, replicative, etc.) collectively known as oncogenic stress, which impact not only on tumor progression, but also on the response to therapy, with profound, multifaceted consequences on clinical outcome. On one hand, recent evidence uncovered a widespread role for MYC in therapy resistance in multiple cancer types, with either standard chemotherapeutic or targeted regimens. Reciprocally, oncogenic MYC imparts a series of molecular and metabolic dependencies to cells, thus giving rise to cancer-specific vulnerabilities that may be exploited to obtain synthetic-lethal interactions with novel anticancer drugs. Here we will review the current knowledge on the links between MYC and therapeutic responses, and will discuss possible strategies to overcome resistance through new, targeted interventions.
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Affiliation(s)
- Giulio Donati
- European Institute of Oncology (IEO) – IRCCSMilanItaly
| | - Bruno Amati
- European Institute of Oncology (IEO) – IRCCSMilanItaly
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18
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Leung HW, Foo G, VanDongen A. Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer’s Disease. Biomedicines 2022; 10:biomedicines10081946. [PMID: 36009494 PMCID: PMC9405677 DOI: 10.3390/biomedicines10081946] [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] [Received: 06/22/2022] [Revised: 07/21/2022] [Accepted: 07/25/2022] [Indexed: 02/06/2023] Open
Abstract
The immediate early gene Arc is a master regulator of synaptic function and a critical determinant of memory consolidation. Here, we show that Arc interacts with dynamic chromatin and closely associates with histone markers for active enhancers and transcription in cultured rat hippocampal neurons. Both these histone modifications, H3K27Ac and H3K9Ac, have recently been shown to be upregulated in late-onset Alzheimer’s disease (AD). When Arc induction by pharmacological network activation was prevented using a short hairpin RNA, the expression profile was altered for over 1900 genes, which included genes associated with synaptic function, neuronal plasticity, intrinsic excitability, and signalling pathways. Interestingly, about 100 Arc-dependent genes are associated with the pathophysiology of AD. When endogenous Arc expression was induced in HEK293T cells, the transcription of many neuronal genes was increased, suggesting that Arc can control expression in the absence of activated signalling pathways. Taken together, these data establish Arc as a master regulator of neuronal activity-dependent gene expression and suggest that it plays a significant role in the pathophysiology of AD.
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Affiliation(s)
| | - Gabriel Foo
- Duke-NUS Medical School, Singapore 169857, Singapore
| | - Antonius VanDongen
- Duke-NUS Medical School, Singapore 169857, Singapore
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
- Correspondence:
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19
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He YY, Zhou HF, Chen L, Wang YT, Xie WL, Xu ZZ, Xiong Y, Feng YQ, Liu GY, Li X, Liu J, Wu QP. The Fra-1: Novel role in regulating extensive immune cell states and affecting inflammatory diseases. Front Immunol 2022; 13:954744. [PMID: 36032067 PMCID: PMC9404335 DOI: 10.3389/fimmu.2022.954744] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 07/22/2022] [Indexed: 11/13/2022] Open
Abstract
Fra-1(Fos-related antigen1), a member of transcription factor activator protein (AP-1), plays an important role in cell proliferation, apoptosis, differentiation, inflammation, oncogenesis and tumor metastasis. Accumulating evidence suggest that the malignancy and invasive ability of tumors can be significantly changed by directly targeting Fra-1. Besides, the effects of Fra-1 are gradually revealed in immune and inflammatory settings, such as arthritis, pneumonia, psoriasis and cardiovascular disease. These regulatory mechanisms that orchestrate immune and non-immune cells underlie Fra-1 as a potential therapeutic target for a variety of human diseases. In this review, we focus on the current knowledge of Fra-1 in immune system, highlighting its unique importance in regulating tissue homeostasis. In addition, we also discuss the possible critical intervention strategy in diseases, which also outline future research and development avenues.
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20
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Julson JR, Marayati R, Beierle EA, Stafman LL. The Role of PIM Kinases in Pediatric Solid Tumors. Cancers (Basel) 2022; 14:3565. [PMID: 35892829 PMCID: PMC9332273 DOI: 10.3390/cancers14153565] [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: 06/22/2022] [Revised: 07/18/2022] [Accepted: 07/21/2022] [Indexed: 12/04/2022] Open
Abstract
PIM kinases have been identified as potential therapeutic targets in several malignancies. Here, we provide an in-depth review of PIM kinases, including their structure, expression, activity, regulation, and role in pediatric carcinogenesis. Also included is a brief summary of the currently available pharmaceutical agents targeting PIM kinases and existing clinical trials.
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Affiliation(s)
- Janet Rae Julson
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (J.R.J.); (R.M.)
| | - Raoud Marayati
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (J.R.J.); (R.M.)
| | - Elizabeth Ann Beierle
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (J.R.J.); (R.M.)
| | - Laura Lee Stafman
- Division of Pediatric Surgery, Department of Surgery, Vanderbilt University, Nashville, TN 37240, USA;
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21
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Yin F, Zhao R, Gorja DR, Fu X, Lu N, Huang H, Xu B, Chen H, Shim JH, Liu K, Li Z, Laster KV, Dong Z, Lee MH. Novel dual inhibitor for targeting PIM1 and FGFR1 kinases inhibits colorectal cancer growth in vitro and patient-derived xenografts in vivo. Acta Pharm Sin B 2022; 12:4122-4137. [PMID: 36386480 PMCID: PMC9643289 DOI: 10.1016/j.apsb.2022.07.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/15/2022] [Accepted: 05/24/2022] [Indexed: 11/30/2022] Open
Abstract
Colorectal cancer (CRC) is the second most common cause of cancer-related death in the world. The pro-viral integration site for Moloney murine leukemia virus 1 (PIM1) is a proto-oncogene and belongs to the serine/threonine kinase family, which are involved in cell proliferation, migration, and apoptosis. Fibroblast growth factor receptor 1 (FGFR1) is a tyrosine kinase that has been implicated in cell proliferation, differentiation and migration. Small molecule HCI-48 is a derivative of chalcone, a class of compounds known to possess anti-tumor, anti-inflammatory and antibacterial effects. However, the underlying mechanism of chalcones against colorectal cancer remains unclear. This study reports that HCI-48 mainly targets PIM1 and FGFR1 kinases, thereby eliciting antitumor effects on colorectal cancer growth in vitro and in vivo. HCI-48 inhibited the activity of both PIM1 and FGFR1 kinases in an ATP-dependent manner, as revealed by computational docking models. Cell-based assays showed that HCI-48 inhibited cell proliferation in CRC cells (HCT-15, DLD1, HCT-116 and SW620), and induced cell cycle arrest in the G2/M phase through modulation of cyclin A2. HCI-48 also induced cellular apoptosis, as evidenced by an increase in the expression of apoptosis biomarkers such as cleaved PARP, cleaved caspase 3 and cleaved caspase 7. Moreover, HCI-48 attenuated the activation of downstream components of the PIM1 and FGFR1 signaling pathways. Using patient-derived xenograft (PDX) murine tumor models, we found that treatment with HCI-48 diminished the PDX tumor growth of implanted CRC tissue expressing high protein levels of PIM1 and FGFR1. This study suggests that the inhibitory effect of HCI-48 on colorectal tumor growth is mainly mediated through the dual-targeting of PIM1 and FGFR1 kinases. This work provides a theoretical basis for the future application of HCI-48 in the treatment of clinical CRC.
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22
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Tinsley SL, Allen-Petersen BL. PP2A and cancer epigenetics: a therapeutic opportunity waiting to happen. NAR Cancer 2022; 4:zcac002. [PMID: 35118387 PMCID: PMC8807117 DOI: 10.1093/narcan/zcac002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 12/08/2021] [Accepted: 01/10/2022] [Indexed: 12/13/2022] Open
Abstract
The epigenetic state of chromatin is altered by regulators which influence gene expression in response to environmental stimuli. While several post-translational modifications contribute to chromatin accessibility and transcriptional programs, our understanding of the role that specific phosphorylation sites play is limited. In cancer, kinases and phosphatases are commonly deregulated resulting in increased oncogenic signaling and loss of epigenetic regulation. Aberrant epigenetic states are known to promote cellular plasticity and the development of therapeutic resistance in many cancer types, highlighting the importance of these mechanisms to cancer cell phenotypes. Protein Phosphatase 2A (PP2A) is a heterotrimeric holoenzyme that targets a diverse array of cellular proteins. The composition of the PP2A complex influences its cellular targets and activity. For this reason, PP2A can be tumor suppressive or oncogenic depending on cellular context. Understanding the nuances of PP2A regulation and its effect on epigenetic alterations can lead to new therapeutic avenues that afford more specificity and contribute to the growth of personalized medicine in the oncology field. In this review, we summarize the known PP2A-regulated substrates and potential phosphorylation sites that contribute to cancer cell epigenetics and possible strategies to therapeutically leverage this phosphatase to suppress tumor growth.
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Affiliation(s)
- Samantha L Tinsley
- Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
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23
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Ou L, Wang X, Cheng S, Zhang M, Cui R, Hu C, Liu S, Tang Q, Peng Y, Chai R, Xie S, Wang S, Huang W, Wang X. Verdinexor, a Selective Inhibitor of Nuclear Exportin 1, Inhibits the Proliferation and Migration of Esophageal Cancer via XPO1/c-Myc/FOSL1 Axis. Int J Biol Sci 2022; 18:276-291. [PMID: 34975332 PMCID: PMC8692140 DOI: 10.7150/ijbs.66612] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 10/29/2021] [Indexed: 12/30/2022] Open
Abstract
Esophageal carcinoma (EC) ranks sixth among cancers in mortality worldwide and effective drugs to reduce EC incidence and mortality are lacking. To explore potential anti-esophageal cancer drugs, we conducted drug screening and discovered that verdinexor, a selective inhibitor of nuclear exportin 1 (XPO1/CRM1), has anti-esophageal cancer effects both in vivo and in vitro. However, the mechanism and role of verdinexor in esophageal cancer remain unknown. In the present study, we observed that verdinexor inhibited the proliferation and migration of EC cells in vitro and suppressed tumor growth in vivo. Additionally, we found that verdinexor induced cleavage of PARP and downregulated XPO1, c-Myc, and FOSL1 expression. RNA-sequence analysis and protein-protein interaction (PPI) analysis revealed that verdinexor regulated the XPO1/c-Myc/FOSL1 axis. The results of immunoprecipitation and proximity ligation assays confirmed that verdinexor disrupted the interaction between XPO1 and c-Myc. Overexpression of c-Myc rescued the inhibition of cell proliferation and cell migration caused by verdinexor. Overexpressed FOSL1 restored the inhibited migration by verdinexor. Taken together, verdinexor inhibited cell proliferation and migration of esophageal cancer via XPO1/c-Myc/FOSL1 axis. Our findings provide a new option for the development of anti-esophageal cancer drugs.
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Affiliation(s)
- Ling Ou
- Bacteriology & Antibacterial Resistance Surveillance Laboratory, Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, Guangdong, China
| | - Xinyou Wang
- The First District of Gastrointestinal Surgery, Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shumin Cheng
- Bacteriology & Antibacterial Resistance Surveillance Laboratory, Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Min Zhang
- Bacteriology & Antibacterial Resistance Surveillance Laboratory, Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Ruiqin Cui
- Bacteriology & Antibacterial Resistance Surveillance Laboratory, Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Chunxia Hu
- Bacteriology & Antibacterial Resistance Surveillance Laboratory, Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Shiyi Liu
- Bacteriology & Antibacterial Resistance Surveillance Laboratory, Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Qian Tang
- Department of Pharmacy, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
- School of Pharmacy, Jinan University, Guangzhou 510630, Guangdong, China
| | - Yuying Peng
- Department of Pharmacy, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
- School of Pharmacy, Jinan University, Guangzhou 510630, Guangdong, China
| | - Ruihuan Chai
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen University, Shenzhen 518000, Guangdong, China
| | - Shouxia Xie
- Department of Pharmacy, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Shaoxiang Wang
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen University, Shenzhen 518000, Guangdong, China
| | - Wei Huang
- Bacteriology & Antibacterial Resistance Surveillance Laboratory, Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Xiao Wang
- Department of Pharmacy, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
- School of Pharmacy, Jinan University, Guangzhou 510630, Guangdong, China
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24
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Llombart V, Mansour MR. Therapeutic targeting of "undruggable" MYC. EBioMedicine 2022; 75:103756. [PMID: 34942444 PMCID: PMC8713111 DOI: 10.1016/j.ebiom.2021.103756] [Citation(s) in RCA: 246] [Impact Index Per Article: 82.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 11/23/2021] [Accepted: 12/01/2021] [Indexed: 12/13/2022] Open
Abstract
c-MYC controls global gene expression and regulates cell proliferation, cell differentiation, cell cycle, metabolism and apoptosis. According to some estimates, MYC is dysregulated in ≈70% of human cancers and strong evidence implicates aberrantly expressed MYC in both tumor initiation and maintenance. In vivo studies show that MYC inhibition elicits a prominent anti-proliferative effect and sustained tumor regression while any alteration on healthy tissue remains reversible. This opens an exploitable window for treatment that makes MYC one of the most appealing therapeutic targets for cancer drug development. This review describes the main functional and structural features of the protein structure of MYC and provides a general overview of the most relevant or recently identified interactors that modulate MYC oncogenic activity. This review also summarizes the different approaches aiming to abrogate MYC oncogenic function, with a particular focus on the prototype inhibitors designed for the direct and indirect targeting of MYC.
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Affiliation(s)
- Victor Llombart
- UCL Cancer Institute, University College London, Department of Haematology, London WC1E 6DD, UK
| | - Marc R Mansour
- UCL Cancer Institute, University College London, Department of Haematology, London WC1E 6DD, UK; UCL Great Ormond Street Institute of Child Health, Developmental Biology and Cancer, London, UK.
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25
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Rathi A, Kumar D, Hasan GM, Haque MM, Hassan MI. Therapeutic targeting of PIM KINASE signaling in cancer therapy: Structural and clinical prospects. Biochim Biophys Acta Gen Subj 2021; 1865:129995. [PMID: 34455019 DOI: 10.1016/j.bbagen.2021.129995] [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: 05/25/2021] [Revised: 07/28/2021] [Accepted: 08/23/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND PIM kinases are well-studied drug targets for cancer, belonging to Serine/Threonine kinases family. They are the downstream target of various signaling pathways, and their up/down-regulation affects various physiological processes. PIM family comprises three isoforms, namely, PIM-1, PIM-2, and PIM-3, on alternative initiation of translation and they have different levels of expression in different types of cancers. Its structure shows a unique ATP-binding site in the hinge region which makes it unique among other kinases. SCOPE OF REVIEW PIM kinases are widely reported in hematological malignancies along with prostate and breast cancers. Currently, many drugs are used as inhibitors of PIM kinases. In this review, we highlighted the physiological significance of PIM kinases in the context of disease progression and therapeutic targeting. We comprehensively reviewed the PIM kinases in terms of their expression and regulation of different physiological roles. We further predicted functional partners of PIM kinases to elucidate their role in the cellular physiology of different cancer and mapped their interaction network. MAJOR CONCLUSIONS A deeper mechanistic insight into the PIM signaling involved in regulating different cellular processes, including transcription, apoptosis, cell cycle regulation, cell proliferation, cell migration and senescence, is provided. Furthermore, structural features of PIM have been dissected to understand the mechanism of inhibition and subsequent implication of designed inhibitors towards therapeutic management of prostate, breast and other cancers. GENERAL SIGNIFICANCE Being a potential drug target for cancer therapy, available drugs and PIM inhibitors at different stages of clinical trials are discussed in detail.
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Affiliation(s)
- Aanchal Rathi
- Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Dhiraj Kumar
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Gulam Mustafa Hasan
- Department of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia
| | | | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
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26
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Sun L, Zhang H, Gao P. Metabolic reprogramming and epigenetic modifications on the path to cancer. Protein Cell 2021; 13:877-919. [PMID: 34050894 PMCID: PMC9243210 DOI: 10.1007/s13238-021-00846-7] [Citation(s) in RCA: 346] [Impact Index Per Article: 86.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023] Open
Abstract
Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence suggests that many metabolites serve as substrates or cofactors of chromatin-modifying enzymes as a consequence of the translocation or spatial regionalization of enzymes or metabolites. Various metabolic alterations and epigenetic modifications also reportedly drive immune escape or impede immunosurveillance within certain contexts, playing important roles in tumor progression. In this review, we focus on how metabolic reprogramming of tumor cells and immune cells reshapes epigenetic alterations, in particular the acetylation and methylation of histone proteins and DNA. We also discuss other eminent metabolic modifications such as, succinylation, hydroxybutyrylation, and lactylation, and update the current advances in metabolism- and epigenetic modification-based therapeutic prospects in cancer.
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Affiliation(s)
- Linchong Sun
- Guangzhou First People's Hospital, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, 510006, China.
| | - Huafeng Zhang
- The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230027, China. .,CAS Centre for Excellence in Cell and Molecular Biology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
| | - Ping Gao
- Guangzhou First People's Hospital, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, 510006, China. .,School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510006, China. .,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510005, China.
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27
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Pellanda P, Dalsass M, Filipuzzi M, Loffreda A, Verrecchia A, Castillo Cano V, Thabussot H, Doni M, Morelli MJ, Soucek L, Kress T, Mazza D, Mapelli M, Beaulieu ME, Amati B, Sabò A. Integrated requirement of non-specific and sequence-specific DNA binding in Myc-driven transcription. EMBO J 2021; 40:e105464. [PMID: 33792944 DOI: 10.15252/embj.2020105464] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 02/15/2021] [Accepted: 02/24/2021] [Indexed: 12/17/2022] Open
Abstract
Eukaryotic transcription factors recognize specific DNA sequence motifs, but are also endowed with generic, non-specific DNA-binding activity. How these binding modes are integrated to determine select transcriptional outputs remains unresolved. We addressed this question by site-directed mutagenesis of the Myc transcription factor. Impairment of non-specific DNA backbone contacts caused pervasive loss of genome interactions and gene regulation, associated with increased intra-nuclear mobility of the Myc protein in murine cells. In contrast, a mutant lacking base-specific contacts retained DNA-binding and mobility profiles comparable to those of the wild-type protein, but failed to recognize its consensus binding motif (E-box) and could not activate Myc-target genes. Incidentally, this mutant gained weak affinity for an alternative motif, driving aberrant activation of different genes. Altogether, our data show that non-specific DNA binding is required to engage onto genomic regulatory regions; sequence recognition in turn contributes to transcriptional activation, acting at distinct levels: stabilization and positioning of Myc onto DNA, and-unexpectedly-promotion of its transcriptional activity. Hence, seemingly pervasive genome interaction profiles, as detected by ChIP-seq, actually encompass diverse DNA-binding modalities, driving defined, sequence-dependent transcriptional responses.
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Affiliation(s)
- Paola Pellanda
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy.,Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy
| | - Mattia Dalsass
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | | | - Alessia Loffreda
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | | | - Virginia Castillo Cano
- Peptomyc S.L., Barcelona, Spain.,Vall d'Hebron Institute of Oncology (VHIO), Edifici Cellex, Barcelona, Spain
| | | | - Mirko Doni
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | - Marco J Morelli
- Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy
| | - Laura Soucek
- Peptomyc S.L., Barcelona, Spain.,Vall d'Hebron Institute of Oncology (VHIO), Edifici Cellex, Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Theresia Kress
- Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy
| | - Davide Mazza
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Marina Mapelli
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | | | - Bruno Amati
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | - Arianna Sabò
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
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28
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Gene Transactivation and Transrepression in MYC-Driven Cancers. Int J Mol Sci 2021; 22:ijms22073458. [PMID: 33801599 PMCID: PMC8037706 DOI: 10.3390/ijms22073458] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 12/11/2022] Open
Abstract
MYC is a proto-oncogene regulating a large number of genes involved in a plethora of cellular functions. Its deregulation results in activation of MYC gene expression and/or an increase in MYC protein stability. MYC overexpression is a hallmark of malignant growth, inducing self-renewal of stem cells and blocking senescence and cell differentiation. This review summarizes the latest advances in our understanding of MYC-mediated molecular mechanisms responsible for its oncogenic activity. Several recent findings indicate that MYC is a regulator of cancer genome and epigenome: MYC modulates expression of target genes in a site-specific manner, by recruiting chromatin remodeling co-factors at promoter regions, and at genome-wide level, by regulating the expression of several epigenetic modifiers that alter the entire chromatin structure. We also discuss novel emerging therapeutic strategies based on both direct modulation of MYC and its epigenetic cofactors.
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29
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Martínez de Paz A, Josefowicz SZ. Signaling-to-chromatin pathways in the immune system. Immunol Rev 2021; 300:37-53. [PMID: 33644906 PMCID: PMC8548991 DOI: 10.1111/imr.12955] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/08/2021] [Accepted: 01/11/2021] [Indexed: 02/01/2023]
Abstract
Complex organisms are able to respond to diverse environmental cues by rapidly inducing specific transcriptional programs comprising a few dozen genes among thousands. The highly complex environment within the nucleus-a crowded milieu containing large genomes tightly condensed with histone proteins in the form of chromatin-makes inducible transcription a challenge for the cell, akin to the proverbial needle in a haystack. The different signaling pathways and transcription factors involved in the transmission of information from the cell surface to the nucleus have been readily explored, but not so much the specific mechanisms employed by the cell to ultimately instruct the chromatin changes necessary for a fast and robust transcription activation. Signaling pathways rely on cascades of protein kinases that, in addition to activating transcription factors can also activate the chromatin template by phosphorylating histone proteins, what we refer to as "signaling-to-chromatin." These pathways appear to be selectively employed and especially critical for driving inducible transcription in macrophages and likely in diverse other immune cell populations. Here, we discuss signaling-to-chromatin pathways with potential relevance in diverse immune cell populations together with chromatin related mechanisms that help to "solve" the needle in a haystack challenge of robust chromatin activation and inducible transcription.
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Affiliation(s)
- Alexia Martínez de Paz
- Laboratory of Epigenetics and Immunity, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Steven Zvi Josefowicz
- Laboratory of Epigenetics and Immunity, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
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30
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IBL-202 is synergistic with venetoclax in CLL under in vitro conditions that mimic the tumor microenvironment. Blood Adv 2020; 4:5093-5106. [PMID: 33085757 DOI: 10.1182/bloodadvances.2019001369] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 09/06/2020] [Indexed: 10/23/2022] Open
Abstract
The B-cell receptor signaling pathway and dysregulation of the Bcl-2 family of proteins play crucial roles in the pathogenesis of chronic lymphocytic leukemia (CLL). Despite significant advances in the treatment of the disease, relapse and drug resistance are not uncommon. In the current study, we investigated the dual PI3/PIM kinase inhibitor IBL-202 in combination with venetoclax as a treatment option for CLL using both primary CLL cells and TP53-deficient OSU-CLL cells generated using the CRISPR-Cas9 system. IBL-202 and venetoclax were highly synergistic against primary CLL cells cocultured with CD40L fibroblasts (combination index [CI], 0.4, at a fractional effect of 0.9) and TP53-knockout (KO) OSU-CLL cells (CI, 0.5, at a fractional effect of 0.9). Synergy between the drugs was consistent, with a significant (P < .05) reduction in the 50% inhibitory concentration for both drugs. IBL-202 and venetoclax in combination induced cell-cycle arrest and slowed the proliferation of both wild-type and TP53-KO cell lines. The drug combination inhibited AKT phosphorylation, reduced expression of Bcl-xL and NF-κB, and increased the Noxa/Mcl-1 ratio. Downregulation of CXCR4 was consistent with inhibition of the SDF-1α-induced migratory capacity of CLL cells. Synergy between IBL-202 and venetoclax against primary CLL cells cultured under conditions that mimic the tumor microenvironment suggests this drug combination may be effective against CLL cells within the lymph nodes and bone marrow. Furthermore, the efficacy of the combination against the TP53-KO OSU-CLL cell line suggests the combination may be a highly effective treatment strategy for high-risk CLL.
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31
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Komar D, Juszczynski P. Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy. Clin Epigenetics 2020; 12:147. [PMID: 33054831 PMCID: PMC7556946 DOI: 10.1186/s13148-020-00941-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 09/28/2020] [Indexed: 12/15/2022] Open
Abstract
Background With the discovery that more than half of human cancers harbor mutations in chromatin proteins, deregulation of epigenetic mechanisms has been recognized a hallmark of malignant transformation. Post-translational modifications (PTMs) of histone proteins, as main components of epigenetic regulatory machinery, are also broadly accepted as therapeutic target. Current “epigenetic” therapies target predominantly writers, erasers and readers of histone acetylation and (to a lesser extent) methylation, leaving other types of PTMs largely unexplored. One of them is the phosphorylation of serine 10 on histone H3 (H3S10ph). Main body H3S10ph is emerging as an important player in the initiation and propagation of cancer, as it facilitates cellular malignant transformation and participates in fundamental cellular functions. In normal cells this histone mark dictates the hierarchy of additional histone modifications involved in the formation of protein binding scaffolds, transcriptional regulation, blocking repressive epigenetic information and shielding gene regions from heterochromatin spreading. During cell division, this mark is essential for chromosome condensation and segregation. It is also involved in the function of specific DNA–RNA hybrids, called R-loops, which modulate transcription and facilitate chromosomal instability. Increase in H3S10ph is observed in numerous cancer types and its abundance has been associated with inferior prognosis. Many H3S10-kinases, including MSK1/2, PIM1, CDK8 and AURORA kinases, have been long considered targets in cancer therapy. However, since these proteins also participate in other critical processes, including signal transduction, apoptotic signaling, metabolic fitness and transcription, their chromatin functions are often neglected. Conclusions H3S10ph and enzymes responsible for deposition of this histone modification are important for chromatin activity and oncogenesis. Epigenetic-drugs targeting this axis of modifications, potentially in combination with conventional or targeted therapy, provide a promising angle in search for knowledge-driven therapeutic strategies in oncology.
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Affiliation(s)
- Dorota Komar
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Gandhi 14 Str, 02-776, Warsaw, Poland.
| | - Przemyslaw Juszczynski
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Gandhi 14 Str, 02-776, Warsaw, Poland
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32
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Wang XY, Sun GB, Wang YJ, Yan F. Emodin Inhibits Resistance to Imatinib by Downregulation of Bcr-Abl and STAT5 and Allosteric Inhibition in Chronic Myeloid Leukemia Cells. Biol Pharm Bull 2020; 43:1526-1533. [DOI: 10.1248/bpb.b20-00325] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Xin-Yi Wang
- Department of Pharmaceutical Analysis, School of pharmacology, China Pharmaceutical University
| | | | - Ya-Jing Wang
- Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University
| | - Fang Yan
- Department of Pharmaceutical Analysis, School of pharmacology, China Pharmaceutical University
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33
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Santio NM, Vainio V, Hoikkala T, Mung KL, Lång M, Vahakoski R, Zdrojewska J, Coffey ET, Kremneva E, Rainio EM, Koskinen PJ. PIM1 accelerates prostate cancer cell motility by phosphorylating actin capping proteins. Cell Commun Signal 2020; 18:121. [PMID: 32771000 PMCID: PMC7414696 DOI: 10.1186/s12964-020-00618-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 06/27/2020] [Indexed: 12/22/2022] Open
Abstract
Background The PIM family kinases promote cancer cell survival and motility as well as metastatic growth in various types of cancer. We have previously identified several PIM substrates, which support cancer cell migration and invasiveness. However, none of them are known to regulate cellular movements by directly interacting with the actin cytoskeleton. Here we have studied the phosphorylation-dependent effects of PIM1 on actin capping proteins, which bind as heterodimers to the fast-growing actin filament ends and stabilize them. Methods Based on a phosphoproteomics screen for novel PIM substrates, we have used kinase assays and fluorescence-based imaging techniques to validate actin capping proteins as PIM1 substrates and interaction partners. We have analysed the functional consequences of capping protein phosphorylation on cell migration and adhesion by using wound healing and real-time impedance-based assays. We have also investigated phosphorylation-dependent effects on actin polymerization by analysing the protective role of capping protein phosphomutants in actin disassembly assays. Results We have identified capping proteins CAPZA1 and CAPZB2 as PIM1 substrates, and shown that phosphorylation of either of them leads to increased adhesion and migration of human prostate cancer cells. Phosphorylation also reduces the ability of the capping proteins to protect polymerized actin from disassembly. Conclusions Our data suggest that PIM kinases are able to induce changes in actin dynamics to support cell adhesion and movement. Thus, we have identified a novel mechanism through which PIM kinases enhance motility and metastatic behaviour of cancer cells.
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