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Wei H, Zheng H, Wang S, Yang Y, Zhao R, Gu A, Hu R, Lan F, Wen W. Targeting redox-sensitive MBD2-NuRD condensate in cancer cells. Nat Cell Biol 2025; 27:801-816. [PMID: 40307576 DOI: 10.1038/s41556-025-01657-2] [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: 07/28/2024] [Accepted: 03/13/2025] [Indexed: 05/02/2025]
Abstract
Transcriptional silencing of hypermethylated tumour suppressor genes is a hallmark of tumorigenesis but the underlying mechanism remains enigmatic. Here we show that methyl-CpG-binding domain protein 2 (MBD2) forms nuclear condensate in diverse cancer cells, where it assembles and navigates the chromatin remodeller NuRD complex to these gene loci for transcriptional suppression, thus fuelling tumour growth. Disturbance of MBD2 condensate reduces the level of NuRD complex-specific proteins, destabilizes heterochromatin foci, facilitates chromatin relaxation and consequently impedes tumour progression. We demonstrate that MBD2 condensate is redox sensitive, mediated by C359. Pro-oxidative interventions disperse MBD2-NuRD condensate, thereby alleviating the transcriptional repression of tumour suppressor genes. Our findings illuminate a hitherto unappreciated function of MBD2 condensate in sustaining a repressive chromatin state essential for cancer cell proliferation and suggest an oxidative stress targeting approach for malignancies with excessive MBD2 condensate.
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Affiliation(s)
- Heyang Wei
- Department of Neurosurgery, Huashan Hospital, the Shanghai Key Laboratory of Medical Epigenetics, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Hongdan Zheng
- Department of Neurosurgery, Huashan Hospital, the Shanghai Key Laboratory of Medical Epigenetics, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Siqing Wang
- Department of Neurosurgery, Huashan Hospital, the Shanghai Key Laboratory of Medical Epigenetics, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yun Yang
- Hangzhou Institute of Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
| | - Ruiqian Zhao
- Department of Neurosurgery, Huashan Hospital, the Shanghai Key Laboratory of Medical Epigenetics, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Aihong Gu
- Department of Neurosurgery, Huashan Hospital, the Shanghai Key Laboratory of Medical Epigenetics, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ronggui Hu
- School of Medicine, Zhejiang University, Hangzhou, China
| | - Fei Lan
- Department of Neurosurgery, Huashan Hospital, the Shanghai Key Laboratory of Medical Epigenetics, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Wenyu Wen
- Department of Neurosurgery, Huashan Hospital, the Shanghai Key Laboratory of Medical Epigenetics, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, China.
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Kajuluri LP, Guo YY, Lee S, Christof M, Malhotra R. Epigenetic Regulation of Human Vascular Calcification. Genes (Basel) 2025; 16:506. [PMID: 40428328 PMCID: PMC12111397 DOI: 10.3390/genes16050506] [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: 03/14/2025] [Revised: 04/24/2025] [Accepted: 04/25/2025] [Indexed: 05/29/2025] Open
Abstract
Vascular diseases present a significant threat to human health worldwide. Atherosclerosis is the most prevalent vascular disease, accounting for the majority of morbidity and mortality globally. Vascular calcification is a dynamic pathological process underlying the development of atherosclerotic plaques and involves the phenotypic transformation of vascular smooth muscle cells (VSMCs) into osteogenic cells. Specifically, the phenotypic switch in VSMCs often involves modifications in gene expression due to epigenetic changes, including DNA methylation, histone modification, and non-coding RNAs. Understanding the role of these epigenetic changes in regulating the pathophysiology of vascular calcification, along with the proteins and pathways that mediate these changes, will aid in identifying new therapeutic candidates to enhance vascular health. This review discusses a comprehensive range of epigenetic modifications and their implications for vascular health and the development of vascular calcification.
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Affiliation(s)
- Lova Prasadareddy Kajuluri
- Cardiovascular Research Center, Heart and Vascular Institute, Mass General Brigham, Boston, MA 02114, USA; (L.P.K.); (Y.Y.G.); (S.L.)
| | - Yugene Young Guo
- Cardiovascular Research Center, Heart and Vascular Institute, Mass General Brigham, Boston, MA 02114, USA; (L.P.K.); (Y.Y.G.); (S.L.)
| | - Sujin Lee
- Cardiovascular Research Center, Heart and Vascular Institute, Mass General Brigham, Boston, MA 02114, USA; (L.P.K.); (Y.Y.G.); (S.L.)
| | - Michael Christof
- School of Arts and Sciences, University of Rochester, Rochester, NY 14627, USA;
| | - Rajeev Malhotra
- Cardiovascular Research Center, Heart and Vascular Institute, Mass General Brigham, Boston, MA 02114, USA; (L.P.K.); (Y.Y.G.); (S.L.)
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3
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Alchaikh Hassan R, Salmasi S, Ghafarzadeh Z, Dasanu CA. Recurrent, multisystem angioedema induced by 5-azacitidine. J Oncol Pharm Pract 2025; 31:503-506. [PMID: 39363705 DOI: 10.1177/10781552241288475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/05/2024]
Abstract
Introduction5-azacitidine is a hypomethylating agent (HMA) used for treating myelodysplastic syndrome (MDS) and certain myeloproliferative neoplasms (MPNs). Common side effects include myelosuppression, nausea and injection site reactions. Serious allergic reactions are rare with this class of agents.Case ReportWe describe a 71-year-old man with MDS/MPN who developed repeated episodes of angioedema after starting treatment with subcutaneous 5-azacitidine. Angioedema involved multiple body areas including the neck, genitalia, lower back and gastrointestinal system. Causality assessment linked this entity to 5-azacitidine via the Naranjo nomogram questionnaire, by scoring 9.Management and Outcome5-azacitidine was discontinued due to recurrent episodes of angioedema that occurred even after dose reduction. Steroids were helpful in terms of reversing this reaction. Afterwards, no further episodes of angioedema have been documented. The patient's thrombocytosis is currently well-controlled with low dose hydroxyurea.Discussion/ConclusionWe report herein a unique case of recurrent, multisystem angioedema likely related to 5-azacitidine. The exact mechanism of azacitidine-induced angioedema is not currently known. Symptoms, clinical findings and timing of presentation are not always clear-cut, and it may take more than one cycle of 5-azacitidine before the diagnosis is made. Supportive and symptomatic treatment will be provided based on the severity of the reaction. Future studies may offer more insights into the mechanism underlying this rare and serious, yet intriguing side effect.
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Affiliation(s)
| | - Shiva Salmasi
- Department of Internal Medicine, Eisenhower Health, Rancho Mirage, CA, USA
| | - Zahra Ghafarzadeh
- Department of Internal Medicine, Eisenhower Health, Rancho Mirage, CA, USA
| | - Constantin A Dasanu
- Lucy Curci Cancer Center, Eisenhower Health, Rancho Mirage, CA, USA
- Department of Medical Oncology and Hematology, University of California in San Diego Health System, San Diego, CA, USA
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4
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Xia X, Kong C, Zhao X, Zhao K, Shi N, Jiang J, Li P. The complexities of cell death mechanisms: a new perspective in systemic sclerosis therapy. Apoptosis 2025; 30:636-651. [PMID: 39924583 DOI: 10.1007/s10495-025-02082-4] [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] [Accepted: 01/21/2025] [Indexed: 02/11/2025]
Abstract
Systemic sclerosis, also termed scleroderma, is a severe and debilitating autoimmune disease characterized by fibrosis, an aberrant immune response, and vascular dysfunction. Cell death is essential to the body's continued normal development as it removes old or damaged cells. This process is governed by several mechanisms, including programmed cell death through apoptosis, necrosis, and pyroptosis, as well as metabolic processes, such as ferroptosis and cuproptosis. This review describes the signaling pathways associated with each form of cell death, examining the linkages between these pathways, and discussing how the dysregulation of cell death processes is involved in the development of autoimmune disorders such as systemic sclerosis. Existing and promising therapeutic strategies aimed at restoring the balance of cell death in systemic sclerosis and other autoimmune disorders are also emphasized.
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Affiliation(s)
- Xue Xia
- Department of Rheumatology and Immunology, China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Chenfei Kong
- Scientific Research Center, China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Xiaoming Zhao
- Scientific Research Center, China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Kelin Zhao
- Department of Rheumatology and Immunology, China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Naixu Shi
- Department of Stomatology, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Jinlan Jiang
- Scientific Research Center, China-Japan Union Hospital, Jilin University, Changchun, 130033, China.
| | - Ping Li
- Department of Rheumatology and Immunology, China-Japan Union Hospital, Jilin University, Changchun, 130033, China.
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Verma SS, Sen CK, Srivastava R, Gnyawali SC, Katiyar P, Sahi AK, Kumar M, Rustagi Y, Liu S, Pandey D, Abouhashem AS, Fehme LNW, Kacar S, Mohanty SK, Faden-McCormack J, Murphy MP, Roy S, Wan J, Yoder MC, Singh K. Tissue nanotransfection-based endothelial PLCγ2-targeted epigenetic gene editing rescues perfusion and diabetic ischemic wound healing. Mol Ther 2025; 33:950-969. [PMID: 39863930 PMCID: PMC11897775 DOI: 10.1016/j.ymthe.2025.01.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 12/16/2024] [Accepted: 01/22/2025] [Indexed: 01/27/2025] Open
Abstract
Diabetic wounds are complicated by underlying peripheral vasculopathy. Reliance on vascular endothelial growth factor (VEGF) therapy to improve perfusion makes logical sense, yet clinical study outcomes on rescuing diabetic wound vascularization have yielded disappointing results. Our previous work has identified that low endothelial phospholipase Cγ2 (PLCγ2) expression hinders the therapeutic effect of VEGF on the diabetic ischemic limb. In this work, guided by single-cell RNA sequencing of human wound edge, we test the efficacy of gene-targeted therapeutic demethylation intending to improve VEGF-mediated neovascularization. PLCγ2 expression was diminished in all five identified diabetic wound-edge endothelial subclusters encompassing arterial, venous, and capillary cells. Such low expression was associated with hypermethylated PLCγ2 promoter. PLCγ2 promoter was also hypermethylated at murine diabetic ischemic wound edge. To specifically demethylate endothelial PLCγ2 promoter during VEGF therapy, a CRISPR-dCas9-based demethylation cocktail was delivered to the ischemic wound edge using tissue nanotransfection (TNT) technology. Demethylation-based upregulation of PLCγ2 during VEGF therapy improved wound tissue blood flow with an increased abundance of von Willebrand factor (vWF)+/PLCγ2+ vascular tissue elements by activating p44/p42-mitogen-activated protein kinase (MAPK) → hypoxia-inducible factor [HIF]-1α pathway. Taken together, TNT-based delivery of plasmids to demethylate the PLCγ2 gene promoter activity led to significant improvements in VEGF therapy for cutaneous diabetic wounds, resulting in better perfusion and accelerated wound closure.
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Affiliation(s)
- Sumit S Verma
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Chandan K Sen
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Rajneesh Srivastava
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Surya C Gnyawali
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Parul Katiyar
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Ajay K Sahi
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Manishekhar Kumar
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Yashika Rustagi
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Sheng Liu
- Center for Computational Biology and Bioinformatics (CCBB), Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Diksha Pandey
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Ahmed S Abouhashem
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Leila N W Fehme
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Sedat Kacar
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Sujit K Mohanty
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Julie Faden-McCormack
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Michael P Murphy
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Sashwati Roy
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Jun Wan
- Center for Computational Biology and Bioinformatics (CCBB), Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Mervin C Yoder
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Kanhaiya Singh
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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Aoki Y, Kubota Y, Masaki N, Tome Y, Bouvet M, Nishida K, Hoffman RM. Targeting Methionine Addiction of Osteosarcoma with Methionine Restriction to Overcome Drug Resistance: A New Paradigm for a Recalcitrant Disease. Cancers (Basel) 2025; 17:506. [PMID: 39941872 PMCID: PMC11817422 DOI: 10.3390/cancers17030506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 01/25/2025] [Accepted: 01/29/2025] [Indexed: 02/16/2025] Open
Abstract
Chemotherapy resistance in osteosarcoma results in a very poor patient prognosis, with the 5-year survival rate of approximately 20%, which not improved for over three decades; thus, the development of novel therapeutic strategies is required. Methionine addiction is a fundamental and general hallmark of cancer, termed the Hoffman effect. Cancer cells need larger amounts of exogenous methionine in order to grow compared to normal cells, despite their ability to synthesize normal or greater amounts of methionine from homocysteine, due to increased transmethylation reactions in cancer cells. Methionine restriction therapy, including recombinant methioninase (rMETase), arrests cancer cells in the late-S/G2 phase of the cell cycle by targeting methionine addiction. First-line chemotherapy for osteosarcoma, including methotrexate (MTX), doxorubicin (DOX), and cisplatinum (CDDP), targets cells in the S/G2-phase, where cancer cells are also inhibited by methionine restriction, resulting in the synergy of methionine restriction to overcome drug resistance. In the present review, we describe the synergistic efficacy of conventional chemotherapy and methionine restriction therapy, including rMETase, in overcoming the drug resistance of osteosarcoma. The clinical potential of this new paradigm to overcome the drug resistance of osteosarcoma is discussed.
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Affiliation(s)
- Yusuke Aoki
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0125, Japan
- AntiCancer Inc., 7917 Ostrow St., Suite B, San Diego, CA 92111, USA
- Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, San Diego, CA 92037, USA
| | - Yutaro Kubota
- AntiCancer Inc., 7917 Ostrow St., Suite B, San Diego, CA 92111, USA
- Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, San Diego, CA 92037, USA
| | - Noriyuki Masaki
- AntiCancer Inc., 7917 Ostrow St., Suite B, San Diego, CA 92111, USA
- Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, San Diego, CA 92037, USA
| | - Yasunori Tome
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0125, Japan
| | - Michael Bouvet
- Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, San Diego, CA 92037, USA
| | - Kotaro Nishida
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0125, Japan
| | - Robert M. Hoffman
- AntiCancer Inc., 7917 Ostrow St., Suite B, San Diego, CA 92111, USA
- Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, San Diego, CA 92037, USA
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Tolu SS, Viny AD, Amengual JE, Pro B, Bates SE. Getting the right combination to break the epigenetic code. Nat Rev Clin Oncol 2025; 22:117-133. [PMID: 39623073 DOI: 10.1038/s41571-024-00972-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2024] [Indexed: 01/26/2025]
Abstract
Rapid advances in the field of epigenetics have facilitated the development of novel therapeutics targeting epigenetic mechanisms that are hijacked by cancer cells to support tumour growth and progression. Several epigenetic agents have been approved by the FDA for the treatment of cancer; however, the efficacy of these drugs is dependent on the underlying biology and drivers of the disease, with inherent differences between solid tumours and haematological malignancies. The efficacy of epigenetic drugs as single agents remains limited across most cancer types, which has spurred the clinical development of combination therapies, with the hope of attaining synergistic activity and/or overcoming treatment resistance. In this Review we discuss clinical advances that have been achieved with the use of epigenetic agents in combination with chemotherapies, immunotherapies or other targeted agents, including epigenetic-epigenetic combinations, as well as limitations and challenges associated with these combinatorial strategies. So far, the success of combination therapies targeting epigenetic mechanisms has generally been confined to haematological malignancies, with limited efficacy observed in patients with solid tumours. Nevertheless, this Review captures the field of epigenetic combination therapies across the spectra of haematology and oncology, highlighting opportunities for precision therapy to effectively harness the potential of epigenetic agents and produce meaningful improvements in clinical outcomes.
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Affiliation(s)
- Seda S Tolu
- Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
| | - Aaron D Viny
- Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Jennifer E Amengual
- Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Barbara Pro
- Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Susan E Bates
- Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
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Scherer B, Bogun L, Koch A, Jäger P, Maus U, Schmitt L, Krings KS, Wesselborg S, Haas R, Schroeder T, Geyh S. Antineoplastic therapy affects the in vitro phenotype and functionality of healthy human bone marrow-derived mesenchymal stromal cells. Arch Toxicol 2025; 99:393-406. [PMID: 39531065 PMCID: PMC11742341 DOI: 10.1007/s00204-024-03898-w] [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: 10/01/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024]
Abstract
While antineoplastic therapies aim to specifically target cancer cells, they may also exert adverse effects on healthy tissues, like healthy hematopoietic stem and progenitor cells (HSPC), leading to hematotoxicity as a common side effect. Mesenchymal stromal cells (MSC) are a major component of the bone marrow (BM) microenvironment, regulating normal hematopoiesis, while their susceptibility to anticancer therapies and contribution to therapy-related hematotoxicity remains largely unexplored. To address this, we investigated the effects of etoposide, temozolomide, 5-azacitidine, and venetoclax on healthy BM-derived MSC functionality. Doses below therapeutic effects of etoposide (0.1-0.25 µM) inhibited cellular growth and induced cellular senescence in healthy MSC, accompanied by an increased mRNA expression of CDKN1A, decreased trilineage differentiation capacity, and insufficient hematopoietic support. Pharmacological doses of 5-azacitidine (2.5 µM) shifted MSC differentiation capacity by inhibiting osteogenic capacity but enhancing the chondrogenic lineage, as demonstrated by histochemical staining and on mRNA level. At the highest clinically relevant dose, neither venetoclax (40 nM) nor temozolomide (100 µM) exerted any effects on MSC but clearly inhibited cellular growth of cancer cell lines and primary healthy HSPC, pointing to damage to hematopoietic cells as a major driver of hematotoxicity of these two compounds. Our findings show that besides HSPC, also MSC are sensitive to certain antineoplastic agents, resulting in molecular and functional alterations that may contribute to therapy-related myelosuppression. Understanding these interactions could be helpful for the development of strategies to preserve BM MSC functionality during different kinds of anticancer therapies.
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Affiliation(s)
- Bo Scherer
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Lucienne Bogun
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Annemarie Koch
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Paul Jäger
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Uwe Maus
- Department of Orthopedic Surgery and Traumatology, Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University, Moorenstraße 5, 40225, Duesseldorf, Germany
| | - Laura Schmitt
- Institute for Molecular Medicine 1, Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University, Universitätsstraße 1, 40225, Duesseldorf, Germany
| | - Karina S Krings
- Institute for Molecular Medicine 1, Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University, Universitätsstraße 1, 40225, Duesseldorf, Germany
| | - Sebastian Wesselborg
- Institute for Molecular Medicine 1, Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University, Universitätsstraße 1, 40225, Duesseldorf, Germany
| | - Rainer Haas
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Thomas Schroeder
- Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Hufelandstraße 55, 45147, Essen, Germany.
| | - Stefanie Geyh
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany.
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Reddy KD, Xenaki D, Adcock IM, Oliver BGG, Zakarya R. Epigenetic Inhibitors Differentially Impact TGF-β1 Signaling Cascades in COPD Airway Smooth Muscle Cells. Cells 2024; 14:31. [PMID: 39791732 PMCID: PMC11720536 DOI: 10.3390/cells14010031] [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: 11/04/2024] [Revised: 12/18/2024] [Accepted: 12/27/2024] [Indexed: 01/12/2025] Open
Abstract
Background: Chronic obstructive pulmonary disease (COPD) is characterized by progressive and incurable airflow obstruction and chronic inflammation. Both TGF-β1 and CXCL8 have been well described as fundamental to COPD progression. DNA methylation and histone acetylation, which are well-understood epigenetic mechanisms regulating gene expression, are associated with COPD progression. However, a deeper understanding of the complex mechanisms associated with DNA methylation, histone post-translational changes and RNA methylation in the context of regulatory pathways remains to be elucidated. We here report on how DNA methylation and histone acetylation inhibition differentially affect CXCL8 signaling in primary human non-COPD and COPD airway cells. Methods: Airway smooth muscle (ASM) cells, a pivotal cell type in COPD, were isolated from the small airways of heavy smokers with and without COPD. Histone acetylation and DNA methylation were inhibited before the TGF-β1 stimulation of cells. Subsequently, CXCL8 production and the abundance and activation of pertinent transcription regulatory proteins (NF-κB, p38 MAPK and JNK) were analyzed. Results: TGF-β1-stimulated CXCL8 release from ASM cells from 'healthy' smoker subjects was significantly modulated by DNA methylation (56.32 pg/mL and 56.60 pg/mL) and acetylation inhibitors (27.50 pg/mL and 48.85 pg/mL) at 24 and 48 h, respectively. However, modulation via the inhibition of DNA methylation (34.06 pg/mL and 43.18 pg/mL) and acetylation (23.14 pg/mL and 27.18 pg/mL) was observed to a lesser extent in COPD ASM cells. These changes were associated with differences in the TGF-β1 activation of NF-κB and MAPK pathways at 10 and 20 min. Conclusions: Our findings offer insight into differential epigenetics in controlling COPD ASM cells and provide a foundation warranting future studies on epigenetic differences associated with COPD diagnosis. This would provide a scope for developing therapeutic interventions targeting signaling and epigenetic pathways to improve patient outcomes.
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Affiliation(s)
- Karosham Diren Reddy
- Respiratory Cellular and Molecular Biology Group, Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, Sydney, NSW 2113, Australia; (D.X.); (B.G.G.O.)
- School of Life Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Dikaia Xenaki
- Respiratory Cellular and Molecular Biology Group, Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, Sydney, NSW 2113, Australia; (D.X.); (B.G.G.O.)
| | - Ian M. Adcock
- Airways Disease, Respiratory Cell & Molecular Biology, Airways Disease Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2BX, UK;
| | - Brian G. G. Oliver
- Respiratory Cellular and Molecular Biology Group, Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, Sydney, NSW 2113, Australia; (D.X.); (B.G.G.O.)
- School of Life Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Razia Zakarya
- School of Life Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
- Epigenetics of Chronic Disease Group, Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, Sydney, NSW 2113, Australia
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10
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Yu S, Li X, Wang T, Li J, Li H, Xu Y, Hu Y, Zhu F, Wang J, Wang T, Zhu B, Zhou XJ, Zhang H, Lv J, Barratt J, Zhao B. B-Cell Epigenetic Modulation of IgA Response by 5-Azacytidine and IgA Nephropathy. J Am Soc Nephrol 2024; 35:1686-1701. [PMID: 39137052 PMCID: PMC11617474 DOI: 10.1681/asn.0000000000000441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 07/26/2024] [Indexed: 08/15/2024] Open
Abstract
Key Points Dysregulated IgA production plays a key role in the pathogenesis of IgA nephropathy. Increased 5-methylcytosine modification, an epigenetic regulatory mechanism, exaggerated IgA nephropathy phenotype in mice. Conversely, inhibition of 5-methylcytosine modification ameliorated progression of IgA nephropathy–like kidney disease in mice. Background IgA nephropathy is an important global cause of kidney failure. Dysregulation of IgA production is believed to play a key role in IgA nephropathy pathogenesis; however, little is known about the epigenetic mechanisms, such as RNA 5-methylcytosine (5mC) modification, in regulating IgA synthesis. Methods To decipher the role of RNA 5mC in regulation of IgA class switch, the microRNA (miR)-23b−/− and Lactobacillus casei (Chinese Industrial Microbial Culture Collection Center) cell wall extract–induced Kawasaki disease mice were treated with 5-azacytidine. Trdmt1 −/− and double Trdmt1 −/−/miR-23b −/− mice and Aid −/− mice or Aid −/−/miR-23b −/− mice were also used. Results We showed that miR-23b downregulated expression of Transfer RNA Aspartic Acid Methyltransferase 1 and consequently reduced 5mC (m5C) RNA modification and IgA synthesis in B cells. Inhibition of m5C RNA modification normalized serum IgA levels and ameliorated progression of the IgA nephropathy–like kidney disease in miR-23b −/− and Kawasaki disease mice, while mesangial IgA and C3 deposition failed to develop in Trdmt1 −/−miR-23b −/− mice. By contrast, increased m5C RNA modification resulted in an exaggerated IgA nephropathy phenotype. miR-23b regulation of serum IgA levels and the development of an IgA nephropathy–like kidney disease in miR-23b −/− and Kawasaki disease mice is likely mediated through TRDMT1-driven 5mC RNA modification in B cells, resulting in impaired activation-induced cytidine deaminase activity and IgA class switch recombination. Conclusions This study revealed TRDMT1-induced RNA 5mC methylation regulated IgA class switch, and inhibition of RNA 5mC by 5-azacytidine ameliorated progression of IgA nephropathy.
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Affiliation(s)
- Shanshan Yu
- Nephrosis Precision Medicine Innovation Center, University of Beihua School of Medicine, Beihua University, Jilin, China
- Department of Nephrology, Zhejiang Provincial People's Hospital, the Affiliated People's Hospital, School of Basic Medicine, Hangzhou Medical College, Hangzhou, China
| | - Xiang Li
- Nephrosis Precision Medicine Innovation Center, University of Beihua School of Medicine, Beihua University, Jilin, China
- Department of Nephrology, Zhejiang Provincial People's Hospital, the Affiliated People's Hospital, School of Basic Medicine, Hangzhou Medical College, Hangzhou, China
| | - Ting Wang
- Nephrosis Precision Medicine Innovation Center, University of Beihua School of Medicine, Beihua University, Jilin, China
| | - Jingyi Li
- Renal Division, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Hongzhi Li
- Nephrosis Precision Medicine Innovation Center, University of Beihua School of Medicine, Beihua University, Jilin, China
| | - Ying Xu
- Renal Division, Jilin University First Hospital, Institute of Nephrology, Jilin University, Changchun, China
| | - Yanling Hu
- Department of Pathology, Liaocheng People's Hospital, Liaocheng, China
| | - Fubin Zhu
- Department of Nephrology, Zhejiang Provincial People's Hospital, the Affiliated People's Hospital, School of Basic Medicine, Hangzhou Medical College, Hangzhou, China
| | - Jinwei Wang
- Renal Division, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Tianhe Wang
- Department of Nephrology, Zhejiang Provincial People's Hospital, the Affiliated People's Hospital, School of Basic Medicine, Hangzhou Medical College, Hangzhou, China
| | - Bin Zhu
- Department of Nephrology, Zhejiang Provincial People's Hospital, the Affiliated People's Hospital, School of Basic Medicine, Hangzhou Medical College, Hangzhou, China
| | - Xu-jie Zhou
- Renal Division, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Hong Zhang
- Renal Division, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Jicheng Lv
- Renal Division, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Jonathan Barratt
- Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
| | - Binghai Zhao
- Nephrosis Precision Medicine Innovation Center, University of Beihua School of Medicine, Beihua University, Jilin, China
- Department of Nephrology, Zhejiang Provincial People's Hospital, the Affiliated People's Hospital, School of Basic Medicine, Hangzhou Medical College, Hangzhou, China
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11
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Stein RA, Gomaa FE, Raparla P, Riber L. Now and then in eukaryotic DNA methylation. Physiol Genomics 2024; 56:741-763. [PMID: 39250426 DOI: 10.1152/physiolgenomics.00091.2024] [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: 07/01/2024] [Accepted: 09/06/2024] [Indexed: 09/11/2024] Open
Abstract
Since the mid-1970s, increasingly innovative methods to detect DNA methylation provided detailed information about its distribution, functions, and dynamics. As a result, new concepts were formulated and older ones were revised, transforming our understanding of the associated biology and catalyzing unprecedented advances in biomedical research, drug development, anthropology, and evolutionary biology. In this review, we discuss a few of the most notable advances, which are intimately intertwined with the study of DNA methylation, with a particular emphasis on the past three decades. Examples of these strides include elucidating the intricacies of 5-methylcytosine (5-mC) oxidation, which are at the core of the reversibility of this epigenetic modification; the three-dimensional structural characterization of eukaryotic DNA methyltransferases, which offered insights into the mechanisms that explain several disease-associated mutations; a more in-depth understanding of DNA methylation in development and disease; the possibility to learn about the biology of extinct species; the development of epigenetic clocks and their use to interrogate aging and disease; and the emergence of epigenetic biomarkers and therapies.
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Affiliation(s)
- Richard A Stein
- Department of Chemical and Biomolecular Engineering, NYU Tandon School of Engineering, Brooklyn, New York, United States
| | - Faris E Gomaa
- Department of Chemical and Biomolecular Engineering, NYU Tandon School of Engineering, Brooklyn, New York, United States
| | - Pranaya Raparla
- Department of Chemical and Biomolecular Engineering, NYU Tandon School of Engineering, Brooklyn, New York, United States
| | - Leise Riber
- Department of Plant and Environmental Sciences, University of Copenhagen, Frederiksberg, Denmark
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12
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González MDR, Chakraborty S, Hernández-Sánchez JM, Diez Campelo M, Park CY, Hernández Rivas JM. Molecular profiling of pre- and post- 5-azacytidine myelodysplastic syndrome samples identifies predictors of response. Front Oncol 2024; 14:1438052. [PMID: 39376992 PMCID: PMC11456566 DOI: 10.3389/fonc.2024.1438052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 08/27/2024] [Indexed: 10/09/2024] Open
Abstract
Treatment with the hypomethylating agent 5-azacytidine (AZA) increases survival in high-risk (HR) myelodysplastic syndrome (MDS) patients, but predicting patient response and overall survival remains challenging. To address these issues, we analyzed mutational and transcriptional profiles in CD34+ hematopoietic stem/progenitor cells (HSPCs) before and following AZA therapy in MDS patients. AZA treatment led to a greater reduction in the mutational burden in both blast and hematological responders than non-responders. Blast and hematological responders showed transcriptional evidence of pre-treatment enrichment for pathways such as oxidative phosphorylation, MYC targets, and mTORC1 signaling. While blast non-response was associated with TNFa signaling and leukemia stem cell signature, hematological non-response was associated with cell-cycle related pathways. AZA induced similar transcriptional responses in MDS patients regardless of response type. Comparison of blast responders and non-responders to normal controls, allowed us to generate a transcriptional classifier that could predict AZA response and survival. This classifier outperformed a previously developed gene signature in a second MDS patient cohort, but signatures of hematological responses were unable to predict survival. Overall, these studies characterize the molecular consequences of AZA treatment in MDS HSPCs and identify a potential tool for predicting AZA therapy responses and overall survival prior to initiation of therapy.
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Affiliation(s)
- Mónica del Rey González
- Institute for Biomedical Research of Salamanca (IBSAL), Institute of Cancer Molecular and Cellular Biology (IBMCC)-Centro de Investigación del Cáncer, Universidad de Salamanca, Salamanca, Spain
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, United States
| | - Sohini Chakraborty
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, United States
| | - Jesús María Hernández-Sánchez
- Institute for Biomedical Research of Salamanca (IBSAL), Institute of Cancer Molecular and Cellular Biology (IBMCC)-Centro de Investigación del Cáncer, Universidad de Salamanca, Salamanca, Spain
| | - María Diez Campelo
- Hematology Department, Hospital Universitario Salamanca, Salamanca, Spain
| | - Christopher Y. Park
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, United States
| | - Jesús María Hernández Rivas
- Institute for Biomedical Research of Salamanca (IBSAL), Institute of Cancer Molecular and Cellular Biology (IBMCC)-Centro de Investigación del Cáncer, Universidad de Salamanca, Salamanca, Spain
- Hematology Department, Hospital Universitario Salamanca, Salamanca, Spain
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13
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Li S, Liang X, Shao Q, Wang G, Huang Y, Wen P, Jiang D, Zeng X. Research hotspots and trends of epigenetic therapy in oncology: a bibliometric analysis from 2004 to 2023. Front Pharmacol 2024; 15:1465954. [PMID: 39329125 PMCID: PMC11424529 DOI: 10.3389/fphar.2024.1465954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 08/30/2024] [Indexed: 09/28/2024] Open
Abstract
Background Epigenetics denotes heritable alterations in gene expression patterns independent of changes in DNA sequence. Epigenetic therapy seeks to reprogram malignant cells to a normal phenotype and has been extensively investigated in oncology. This study conducts a bibliometric analysis of epigenetic therapy in cancer, providing a comprehensive overview of current research, identifying trends, and highlighting key areas of investigation. Methods Publications concerning epigenetic inhibitors in cancer spanning 2004 to 2023 were retrieved from the Web of Science Core Collection (WoSCC). Co-occurrence analysis using VOSviewer assessed current status and focal points. Evolutionary trends and bursts in the knowledge domain were analyzed using CiteSpace. Bibliometrix facilitated topic evolution and revealed trends in keywords. National, institutional, and author affiliations and collaborations were also examined. Results A total of 2,153 articles and reviews on epigenetic therapy in oncology were identified, demonstrating a consistent upward trend over time. The United States (745 papers), University of Texas MD Anderson Cancer Center (57 papers), and Stephen B. Baylin (27 papers) emerged as the most productive country, institution, and author, respectively. Keyword co-occurrence analysis identified five primary clusters: tumor, DNA methylation, epigenetic therapy, expression, and immunotherapy. In the past 5 years, newly emerging themes with increased centrality and density include "drug resistance," "immunotherapy," and "combination therapy." The most cited publication reviewed current understanding of potential causes of epigenetic diseases and proposed future therapeutic strategies. Conclusion In the past two decades, the importance of epigenetic therapy in cancer research has become increasingly prominent. The United States occupies a key position in this field, while China, despite having published a large number of related papers, still has relatively limited influence. Current research focuses on the "combination therapy" of epigenetic drugs. Future studies should further explore the sequencing and scheduling of combination therapies, optimize trial designs and dosing regimens to improve clinical efficacy.
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Affiliation(s)
- Sisi Li
- Department of Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, China
- Chongqing Key Laboratory for Intelligent Oncology in Breast Cancer (iCQBC), Chongqing University Cancer Hospital, Chongqing, China
| | - Xinrui Liang
- Department of Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Qing Shao
- Department of Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, China
- Chongqing Key Laboratory for Intelligent Oncology in Breast Cancer (iCQBC), Chongqing University Cancer Hospital, Chongqing, China
| | - Guanwen Wang
- Department of Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, China
- Chongqing Key Laboratory for Intelligent Oncology in Breast Cancer (iCQBC), Chongqing University Cancer Hospital, Chongqing, China
| | - Yuxin Huang
- School of Medicine, Chongqing University, Chongqing, China
| | - Ping Wen
- School of Medicine, Chongqing University, Chongqing, China
| | - Dongping Jiang
- School of Medicine, Chongqing University, Chongqing, China
| | - Xiaohua Zeng
- Department of Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, China
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14
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Silva-Hurtado TJ, Inocencio JF, Yong RL. Emerging applications of hypomethylating agents in the treatment of glioblastoma (Review). Mol Clin Oncol 2024; 21:59. [PMID: 39006906 PMCID: PMC11240870 DOI: 10.3892/mco.2024.2757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 04/26/2024] [Indexed: 07/16/2024] Open
Abstract
DNA hypomethylating agents (HMAs) such as decitabine and 5-azacytidine have established roles in the treatment paradigms for myelodysplastic syndrome and acute myelogenous leukemia, where they are considered to exert their anticancer effects by restoring the expression of tumor suppressor genes. Due to their relatively favorable adverse effect profile and known ability to pass through the blood-brain barrier, applications in the treatment of glioblastoma (GBM) and other central nervous system malignancies are under active investigation. The present review examines the types of HMAs currently available, their known and less-understood antineoplastic mechanisms, and the evidence to date of their preclinical and clinical efficacy in glioblastoma and other solid malignancies. The present review discusses the potential synergies HMAs may have with established and emerging GBM treatments, including temozolomide, immune checkpoint inhibitors and cancer vaccines. Recent successes and setbacks in clinical trials for newly diagnosed and recurrent GBM are summarized in order to highlight opportunities for HMAs to improve therapeutic responses. Challenges for future clinical trials are also assessed.
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Affiliation(s)
- Thenzing J. Silva-Hurtado
- Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Julio F. Inocencio
- Leo M. Davidoff Department of Neurosurgery, Montefiore Medical Center, Einstein College of Medicine, Bronx, NY 10461, USA
| | - Raymund L. Yong
- Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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15
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Liu J, Ruan M, Liu Y, Hong X, Zhang L, Zhang Q. Identification of 3-(9H-carbazol-9-yl)-2-(1,3-dioxoisoindolin-2-yl)propanoic acids as promising DNMT1 inhibitors. Eur J Med Chem 2024; 274:116538. [PMID: 38823264 DOI: 10.1016/j.ejmech.2024.116538] [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: 03/28/2024] [Revised: 05/12/2024] [Accepted: 05/26/2024] [Indexed: 06/03/2024]
Abstract
DNA methyltransferase 1 (DNMT1) is the primary enzyme responsible for maintaining DNA methylation patterns during cellular division, crucial for cancer development by suppressing tumor suppressor genes. In this study, we retained the phthalimide structure of N-phthaloyl-l-tryptophan (RG108) and substituted its indole ring with nitrogen-containing aromatic rings of varying sizes. We synthesized 3-(9H-carbazol-9-yl)-2-(1,3-dioxoisoindolin-2-yl)propanoic acids and confirmed them as DNMT1 inhibitors through protein affinity testing, radiometric method using tritium labeled SAM, and MTT assay. Preliminary structure-activity relationship analysis revealed that introducing substituents on the carbazole ring could enhance inhibitory activity, with S-configuration isomers showing greater activity than R-configuration ones. Notably, S-3-(3,6-di-tert-butyl-9H-carbazol-9-yl)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (7r-S) and S-3-(1,3,6-trichloro-9H-carbazol-9-yl)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (7t-S) exhibited significant DNMT1 enzyme inhibition activity, with IC50 values of 8.147 μM and 0.777 μM, respectively (compared to RG108 with an IC50 above 250 μM). Moreover, they demonstrated potential anti-proliferative activity on various tumor cell lines including A2780, HeLa, K562, and SiHa. Transcriptome analysis and KEGG pathway enrichment of K562 cells treated with 7r-S and 7t-S identified differentially expressed genes (DEGs) related to apoptosis and cell cycle pathways. Flow cytometry assays further indicated that 7r-S and 7t-S induce apoptosis in K562 cells and arrest them in the G0/G1 phase in a concentration-dependent manner. Molecular docking revealed that 7t-S may bind to the methyl donor S-adenosyl-l-methionine (SAM) site in DNMT1 with an orientation opposite to RG108, suggesting potential for deeper penetration into the DNMT1 pocket and laying the groundwork for further modifications.
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Affiliation(s)
- Jingyi Liu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Minli Ruan
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Yueqin Liu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Xiaoqian Hong
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Lijun Zhang
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Qian Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China.
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16
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Rodriguez-Tirado C, Sosa MS. How much do we know about the metastatic process? Clin Exp Metastasis 2024; 41:275-299. [PMID: 38520475 PMCID: PMC11374507 DOI: 10.1007/s10585-023-10248-0] [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: 08/13/2023] [Accepted: 11/17/2023] [Indexed: 03/25/2024]
Abstract
Cancer cells can leave their primary sites and travel through the circulation to distant sites, where they lodge as disseminated cancer cells (DCCs), even during the early and asymptomatic stages of tumor progression. In experimental models and clinical samples, DCCs can be detected in a non-proliferative state, defined as cellular dormancy. This state can persist for extended periods until DCCs reawaken, usually in response to niche-derived reactivation signals. Therefore, their clinical detection in sites like lymph nodes and bone marrow is linked to poor survival. Current cancer therapy designs are based on the biology of the primary tumor and do not target the biology of the dormant DCC population and thus fail to eradicate the initial or subsequent waves of metastasis. In this brief review, we discuss the current methods for detecting DCCs and highlight new strategies that aim to target DCCs that constitute minimal residual disease to reduce or prevent metastasis formation. Furthermore, we present current evidence on the relevance of DCCs derived from early stages of tumor progression in metastatic disease and describe the animal models available for their study. We also discuss our current understanding of the dissemination mechanisms utilized by genetically less- and more-advanced cancer cells, which include the functional analysis of intermediate or hybrid states of epithelial-mesenchymal transition (EMT). Finally, we raise some intriguing questions regarding the clinical impact of studying the crosstalk between evolutionary waves of DCCs and the initiation of metastatic disease.
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Affiliation(s)
- Carolina Rodriguez-Tirado
- Department of Microbiology and Immunology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
- Department of Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
- Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
- Cancer Dormancy and Tumor Microenvironment Institute/Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
- Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
| | - Maria Soledad Sosa
- Department of Microbiology and Immunology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
- Department of Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
- Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
- Cancer Dormancy and Tumor Microenvironment Institute/Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
- Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.
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17
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Wang L, Bai Y, Cao Z, Guo Z, Lian Y, Liu P, Zeng Y, Lyu W, Chen Q. Histone deacetylases and inhibitors in diabetes mellitus and its complications. Biomed Pharmacother 2024; 177:117010. [PMID: 38941890 DOI: 10.1016/j.biopha.2024.117010] [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: 04/11/2024] [Revised: 05/29/2024] [Accepted: 06/17/2024] [Indexed: 06/30/2024] Open
Abstract
Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, with its prevalence linked to both genetic predisposition and environmental factors. Epigenetic modifications, particularly through histone deacetylases (HDACs), have been recognized for their significant influence on DM pathogenesis. This review focuses on the classification of HDACs, their role in DM and its complications, and the potential therapeutic applications of HDAC inhibitors. HDACs, which modulate gene expression without altering DNA sequences, are categorized into four classes with distinct functions and tissue specificity. HDAC inhibitors (HDACi) have shown efficacy in various diseases, including DM, by targeting these enzymes. The review highlights how HDACs regulate β-cell function, insulin sensitivity, and hepatic gluconeogenesis in DM, as well as their impact on diabetic cardiomyopathy, nephropathy, and retinopathy. Finally, we suggest that targeted histone modification is expected to become a key method for the treatment of diabetes and its complications. The study of HDACi offers insights into new treatment strategies for DM and its associated complications.
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Affiliation(s)
- Li Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610072, PR China; Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, PR China
| | - Yuning Bai
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, PR China
| | - Zhengmin Cao
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, PR China
| | - Ziwei Guo
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, PR China
| | - Yanjie Lian
- Department of Cardiovascular Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, PR China
| | - Pan Liu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610072, PR China
| | - Yixian Zeng
- Department of Proctology, Beibei Hospital of Traditional Chinese Medicine, Chongqing 400799, PR China
| | - Wenliang Lyu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, PR China.
| | - Qiu Chen
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610072, PR China.
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18
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Xiong HY, Wyns A, Campenhout JV, Hendrix J, De Bruyne E, Godderis L, Schabrun S, Nijs J, Polli A. Epigenetic Landscapes of Pain: DNA Methylation Dynamics in Chronic Pain. Int J Mol Sci 2024; 25:8324. [PMID: 39125894 PMCID: PMC11312850 DOI: 10.3390/ijms25158324] [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: 06/30/2024] [Revised: 07/19/2024] [Accepted: 07/23/2024] [Indexed: 08/12/2024] Open
Abstract
Chronic pain is a prevalent condition with a multifaceted pathogenesis, where epigenetic modifications, particularly DNA methylation, might play an important role. This review delves into the intricate mechanisms by which DNA methylation and demethylation regulate genes associated with nociception and pain perception in nociceptive pathways. We explore the dynamic nature of these epigenetic processes, mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes, which modulate the expression of pro- and anti-nociceptive genes. Aberrant DNA methylation profiles have been observed in patients with various chronic pain syndromes, correlating with hypersensitivity to painful stimuli, neuronal hyperexcitability, and inflammatory responses. Genome-wide analyses shed light on differentially methylated regions and genes that could serve as potential biomarkers for chronic pain in the epigenetic landscape. The transition from acute to chronic pain is marked by rapid DNA methylation reprogramming, suggesting its potential role in pain chronicity. This review highlights the importance of understanding the temporal dynamics of DNA methylation during this transition to develop targeted therapeutic interventions. Reversing pathological DNA methylation patterns through epigenetic therapies emerges as a promising strategy for pain management.
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Affiliation(s)
- Huan-Yu Xiong
- Pain in Motion Research Group (PAIN), Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (H.-Y.X.); (A.W.); (J.V.C.); (J.H.); (A.P.)
| | - Arne Wyns
- Pain in Motion Research Group (PAIN), Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (H.-Y.X.); (A.W.); (J.V.C.); (J.H.); (A.P.)
| | - Jente Van Campenhout
- Pain in Motion Research Group (PAIN), Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (H.-Y.X.); (A.W.); (J.V.C.); (J.H.); (A.P.)
| | - Jolien Hendrix
- Pain in Motion Research Group (PAIN), Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (H.-Y.X.); (A.W.); (J.V.C.); (J.H.); (A.P.)
- Department of Public Health and Primary Care, Centre for Environment & Health, KU Leuven, 3000 Leuven, Belgium;
- Research Foundation—Flanders (FWO), 1000 Brussels, Belgium
| | - Elke De Bruyne
- Translational Oncology Research Center (TORC), Team Hematology and Immunology (HEIM), Vrije Universiteit Brussel, 1090 Brussels, Belgium;
| | - Lode Godderis
- Department of Public Health and Primary Care, Centre for Environment & Health, KU Leuven, 3000 Leuven, Belgium;
| | - Siobhan Schabrun
- The School of Physical Therapy, University of Western Ontario, London, ON N6A 3K7, Canada;
- The Gray Centre for Mobility and Activity, Parkwood Institute, St. Joseph’s Healthcare, London, ON N6A 4V2, Canada
| | - Jo Nijs
- Pain in Motion Research Group (PAIN), Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (H.-Y.X.); (A.W.); (J.V.C.); (J.H.); (A.P.)
- Chronic Pain Rehabilitation, Department of Physical Medicine and Physiotherapy, University Hospital Brussels, 1090 Brussels, Belgium
- Department of Health and Rehabilitation, Unit of Physiotherapy, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 41390 Göterbog, Sweden
| | - Andrea Polli
- Pain in Motion Research Group (PAIN), Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (H.-Y.X.); (A.W.); (J.V.C.); (J.H.); (A.P.)
- Department of Public Health and Primary Care, Centre for Environment & Health, KU Leuven, 3000 Leuven, Belgium;
- Research Foundation—Flanders (FWO), 1000 Brussels, Belgium
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19
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Hu D, Zhao T, Xu C, Pan X, Zhou Z, Wang S. Epigenetic Modifiers in Cancer Metastasis. Biomolecules 2024; 14:916. [PMID: 39199304 PMCID: PMC11352731 DOI: 10.3390/biom14080916] [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: 06/03/2024] [Revised: 07/18/2024] [Accepted: 07/25/2024] [Indexed: 09/01/2024] Open
Abstract
Metastasis is the primary cause of cancer-related death, with the dissemination and colonization of primary tumor cells at the metastatic site facilitated by various molecules and complex pathways. Understanding the biological mechanisms underlying the metastatic process is critical for the development of effective interventions. Several epigenetic modifications have been identified that play critical roles in regulating cancer metastasis. This review aims to provide a comprehensive summary of recent advances in understanding the role of epigenetic modifiers, including histone modifications, DNA methylation, non-coding RNAs, enhancer reprogramming, chromatin accessibility, and N6-methyladenosine, in metastasis-associated processes, such as epithelial-mesenchymal transition (EMT), cancer cell migration, and invasion. In particular, this review provides a detailed and in-depth description of the role of crosstalk between epigenetic regulators in tumor metastasis. Additionally, we explored the potential and limitations of epigenetics-related target molecules in the diagnosis, treatment, and prognosis of cancer metastasis.
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Affiliation(s)
- Die Hu
- Key Laboratory of Molecular Genetics between Kangda College of Nanjing Medical University and Suzhou Medical College of Soochow University, Suzhou 215123, China;
- Department of Basic Medicine, Kangda College of Nanjing Medical University, Lianyungang 222000, China; (C.X.); (X.P.)
| | - Tianci Zhao
- Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110122, China;
| | - Chenxing Xu
- Department of Basic Medicine, Kangda College of Nanjing Medical University, Lianyungang 222000, China; (C.X.); (X.P.)
| | - Xinyi Pan
- Department of Basic Medicine, Kangda College of Nanjing Medical University, Lianyungang 222000, China; (C.X.); (X.P.)
| | - Zhengyu Zhou
- Key Laboratory of Molecular Genetics between Kangda College of Nanjing Medical University and Suzhou Medical College of Soochow University, Suzhou 215123, China;
- Laboratory Animal Center, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Shengjie Wang
- Key Laboratory of Molecular Genetics between Kangda College of Nanjing Medical University and Suzhou Medical College of Soochow University, Suzhou 215123, China;
- Department of Basic Medicine, Kangda College of Nanjing Medical University, Lianyungang 222000, China; (C.X.); (X.P.)
- Laboratory Animal Center, Suzhou Medical College of Soochow University, Suzhou 215123, China
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20
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Poltronieri P. Regulatory RNAs: role as scaffolds assembling protein complexes and their epigenetic deregulation. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:841-876. [PMID: 39280246 PMCID: PMC11390297 DOI: 10.37349/etat.2024.00252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 04/26/2024] [Indexed: 09/18/2024] Open
Abstract
Recently, new data have been added to the interaction between non-coding RNAs (ncRNAs) and epigenetic machinery. Epigenetics includes enzymes involved in DNA methylation, histone modifications, and RNA modifications, and mechanisms underlying chromatin structure, repressive states, and active states operating in transcription. The main focus is on long ncRNAs (lncRNAs) acting as scaffolds to assemble protein complexes. This review does not cover RNA's role in sponging microRNAs, or decoy functions. Several lncRNAs were shown to regulate chromatin activation and repression by interacting with Polycomb repressive complexes and mixed-lineage leukemia (MLL) activating complexes. Various groups reported on enhancer of zeste homolog 2 (EZH2) interactions with regulatory RNAs. Knowledge of the function of these complexes opens the perspective to develop new therapeutics for cancer treatment. Lastly, the interplay between lncRNAs and epitranscriptomic modifications in cancers paves the way for new targets in cancer therapy. The approach to inhibit lncRNAs interaction with protein complexes and perspective to regulate epitrascriptomics-regulated RNAs may bring new compounds as therapeuticals in various types of cancer.
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Affiliation(s)
- Palmiro Poltronieri
- Agrofood Department, National Research Council, CNR-ISPA, 73100 Lecce, Italy
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21
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Dada T, Mahalingam K, Bhartiya S. Reversing Aging and Improving Health Span in Glaucoma Patients: The Next Frontier? J Curr Glaucoma Pract 2024; 18:87-93. [PMID: 39575133 PMCID: PMC11576344 DOI: 10.5005/jp-journals-10078-1451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2024] Open
Abstract
How to cite this article: Dada T, Mahalingam K, Bhartiya S. Reversing Aging and Improving Health Span in Glaucoma Patients: The Next Frontier? J Curr Glaucoma Pract 2024;18(3):87-93.
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Affiliation(s)
- Tanuj Dada
- Department of Ophthalmology, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Delhi, India
| | - Karthikeyan Mahalingam
- Department of Ophthalmology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Shibal Bhartiya
- Department of Ophthalmology and Community Outreach, Marengo Asia Hospitals, Gurugram and Faridabad, Haryana, India; Mayo Clinic, Jacksonville, Florida, United States
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22
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Lee AV, Nestler KA, Chiappinelli KB. Therapeutic targeting of DNA methylation alterations in cancer. Pharmacol Ther 2024; 258:108640. [PMID: 38570075 DOI: 10.1016/j.pharmthera.2024.108640] [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: 12/13/2023] [Revised: 03/13/2024] [Accepted: 03/22/2024] [Indexed: 04/05/2024]
Abstract
DNA methylation is a critical component of gene regulation and plays an important role in the development of cancer. Hypermethylation of tumor suppressor genes and silencing of DNA repair pathways facilitate uncontrolled cell growth and synergize with oncogenic mutations to perpetuate cancer phenotypes. Additionally, aberrant DNA methylation hinders immune responses crucial for antitumor immunity. Thus, inhibiting dysregulated DNA methylation is a promising cancer therapy. Pharmacologic inhibition of DNA methylation reactivates silenced tumor suppressors and bolster immune responses through induction of viral mimicry. Now, with the advent of immunotherapies and discovery of the immune-modulatory effects of DNA methylation inhibitors, there is great interest in understanding how targeting DNA methylation in combination with other therapies can enhance antitumor immunity. Here, we describe the role of aberrant DNA methylation in cancer and mechanisms by which it promotes tumorigenesis and modulates immune responses. Finally, we review the initial discoveries and ongoing efforts to target DNA methylation as a cancer therapeutic.
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Affiliation(s)
- Abigail V Lee
- Department of Microbiology, Immunology, & Tropical Medicine, The George Washington University, Washington, DC, USA
| | - Kevin A Nestler
- Department of Microbiology, Immunology, & Tropical Medicine, The George Washington University, Washington, DC, USA
| | - Katherine B Chiappinelli
- Department of Microbiology, Immunology, & Tropical Medicine, The George Washington University, Washington, DC, USA.
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23
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Lundstrom K. Epigenetics: rethinking of drug research and development. Future Med Chem 2024; 16:2321-2323. [PMID: 31741399 PMCID: PMC11622805 DOI: 10.4155/fmc-2019-0174] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 10/04/2019] [Indexed: 12/20/2022] Open
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24
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Su K, Vázquez O. Enlightening epigenetics: optochemical tools illuminate the path. Trends Biochem Sci 2024; 49:290-304. [PMID: 38350805 DOI: 10.1016/j.tibs.2024.01.003] [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: 10/04/2023] [Revised: 12/20/2023] [Accepted: 01/10/2024] [Indexed: 02/15/2024]
Abstract
Optochemical tools have become potent instruments for understanding biological processes at the molecular level, and the past decade has witnessed their use in epigenetics and epitranscriptomics (also known as RNA epigenetics) for deciphering gene expression regulation. By using photoresponsive molecules such as photoswitches and photocages, researchers can achieve precise control over when and where specific events occur. Therefore, these are invaluable for studying both histone and nucleotide modifications and exploring disease-related mechanisms. We systematically report and assess current examples in the field, and identify open challenges and future directions. These outstanding proof-of-concept investigations will inspire other chemical biologists to participate in these emerging fields given the potential of photochromic molecules in research and biomedicine.
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Affiliation(s)
- Kaijun Su
- Department of Chemistry, University of Marburg, Marburg D-35043, Germany
| | - Olalla Vázquez
- Department of Chemistry, University of Marburg, Marburg D-35043, Germany; Center for Synthetic Microbiology (SYNMIKRO), University of Marburg, Marburg D-35043, Germany.
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25
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Lee M, Ahmad SF, Xu J. Regulation and function of transposable elements in cancer genomes. Cell Mol Life Sci 2024; 81:157. [PMID: 38556602 PMCID: PMC10982106 DOI: 10.1007/s00018-024-05195-2] [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: 12/03/2023] [Revised: 02/28/2024] [Accepted: 03/01/2024] [Indexed: 04/02/2024]
Abstract
Over half of human genomic DNA is composed of repetitive sequences generated throughout evolution by prolific mobile genetic parasites called transposable elements (TEs). Long disregarded as "junk" or "selfish" DNA, TEs are increasingly recognized as formative elements in genome evolution, wired intimately into the structure and function of the human genome. Advances in sequencing technologies and computational methods have ushered in an era of unprecedented insight into how TE activity impacts human biology in health and disease. Here we discuss the current views on how TEs have shaped the regulatory landscape of the human genome, how TE activity is implicated in human cancers, and how recent findings motivate novel strategies to leverage TE activity for improved cancer therapy. Given the crucial role of methodological advances in TE biology, we pair our conceptual discussions with an in-depth review of the inherent technical challenges in studying repeats, specifically related to structural variation, expression analyses, and chromatin regulation. Lastly, we provide a catalog of existing and emerging assays and bioinformatic software that altogether are enabling the most sophisticated and comprehensive investigations yet into the regulation and function of interspersed repeats in cancer genomes.
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Affiliation(s)
- Michael Lee
- Department of Pediatrics, Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX, 75390, USA.
| | - Syed Farhan Ahmad
- Department of Pathology, Center of Excellence for Leukemia Studies, St. Jude Children's Research Hospital, 262 Danny Thomas Place - MS 345, Memphis, TN, 38105, USA
| | - Jian Xu
- Department of Pathology, Center of Excellence for Leukemia Studies, St. Jude Children's Research Hospital, 262 Danny Thomas Place - MS 345, Memphis, TN, 38105, USA.
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26
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Pereira B, Correia FP, Alves IA, Costa M, Gameiro M, Martins AP, Saraiva JA. Epigenetic reprogramming as a key to reverse ageing and increase longevity. Ageing Res Rev 2024; 95:102204. [PMID: 38272265 DOI: 10.1016/j.arr.2024.102204] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/18/2023] [Accepted: 01/19/2024] [Indexed: 01/27/2024]
Abstract
The pursuit for the fountain of youth has long been a fascination amongst scientists and humanity. Ageing is broadly characterized by a cellular decline with increased susceptibility to age-related diseases, being intimately associated with epigenetic modifications. Recently, reprogramming-induced rejuvenation strategies have begun to greatly alter longevity research not only to tackle age-related defects but also to possibly reverse the cellular ageing process. Hence, in this review, we highlight the major epigenetic changes during ageing and the state-of-art of the current emerging epigenetic reprogramming strategies leveraging on transcription factors. Notably, partial reprogramming enables the resetting of the ageing clock without erasing cellular identity. Promising chemical-based rejuvenation strategies harnessing small molecules, including DNA methyltransferase and histone deacetylase inhibitors are also discussed. Moreover, in parallel to longevity interventions, the foundations of epigenetic clocks for accurate ageing assessment and evaluation of reprogramming approaches are briefly presented. Going further, with such scientific breakthroughs, we are witnessing a rise in the longevity biotech industry aiming to extend the health span and ideally achieve human rejuvenation one day. In this context, we overview the main scenarios proposed for the future of the socio-economic and ethical challenges associated with such an emerging field. Ultimately, this review aims to inspire future research on interventions that promote healthy ageing for all.
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Affiliation(s)
- Beatriz Pereira
- Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | | | - Inês A Alves
- Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Margarida Costa
- Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Mariana Gameiro
- Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Ana P Martins
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Jorge A Saraiva
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal.
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27
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Jumaniyazova E, Aghajanyan A, Kurevlev S, Tskhovrebova L, Makarov A, Gordon K, Lokhonina A, Fatkhudinov T. SP1 Gene Methylation in Head and Neck Squamous Cell Cancer in HPV-Negative Patients. Genes (Basel) 2024; 15:281. [PMID: 38540340 PMCID: PMC10970621 DOI: 10.3390/genes15030281] [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: 01/29/2024] [Revised: 02/17/2024] [Accepted: 02/21/2024] [Indexed: 04/02/2024] Open
Abstract
There is still much to learn about the epigenetic mechanisms controlling gene expression during carcinogenesis. When researching aberrant DNA methylation, active proliferative tumor cells from head and neck squamous cell cancer (HNSCC) can be used as a model. The aim of the study was to investigate the methylation status of CDKN1, CDKN2A, MYC, Smad3, SP1, and UBC genes in tumor tissue (control-normal tissue) in 50 patients (37 men and 13 women) with HPV-negative HNSCC. Methods: Bisulfite conversion methods and methyl-sensitive analysis of high-resolution melting curves were used to quantify the methylation of genes. In all patients and across various subgroups (tongue carcinoma, laryngeal and other types of carcinomas T2, T3, T4 status; age before and after 50 years; smoking and non-smoking), there are consistent differences in the methylation levels in the SP1 gene in tumor DNA compared to normal. Results: The methylation of the SP1 gene in tumor DNA suppresses its expression, hinders HNSCC cell proliferation regulation, and could be a molecular indicator of malignant cell growth. The study of DNA methylation of various genes involved in carcinogenesis is promising because hypermethylated promoters can serve as potential biomarkers of disease.
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Affiliation(s)
- Enar Jumaniyazova
- Institute of Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
| | - Anna Aghajanyan
- Institute of Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
| | - Sergey Kurevlev
- Institute of Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
| | - Leyla Tskhovrebova
- Institute of Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
| | - Andrey Makarov
- Institute of Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
- Histology Department, Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 117997 Moscow, Russia
| | - Konstantin Gordon
- Institute of Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
- A. Tsyb Medical Radiological Research Center, Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation (A. Tsyb MRRC), 4, Korolev Street, 249036 Obninsk, Russia
| | - Anastasiya Lokhonina
- Institute of Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
| | - Timur Fatkhudinov
- Institute of Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
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28
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Bouligny IM, Murray G, Doyel M, Patel T, Boron J, Tran V, Gor J, Hang Y, Alnimer Y, Ho T, Zacholski K, Venn C, Wages NA, Grant S, Maher KR. Venetoclax with decitabine or azacitidine in relapsed or refractory acute myeloid leukemia. Med Oncol 2024; 41:80. [PMID: 38396145 DOI: 10.1007/s12032-024-02302-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 01/11/2024] [Indexed: 02/25/2024]
Abstract
Relapsed or refractory acute myeloid leukemia (AML) is associated with poor outcomes and resistance to therapy. The addition of venetoclax, a BCL-2 antagonist, to lower-intensity therapies results in improved survival in the first-line setting compared to monotherapy with a hypomethylating agent or low-dose cytarabine. Despite this, much remains unknown about the performance of venetoclax with a hypomethylating agent following the first-line setting. Additionally, while the ELN 2022 guidelines appear to improve the prognostication of AML, clarification is needed to determine how the revision applies to lower-intensity strategies. To investigate this, we retrospectively analyzed the performance of venetoclax with decitabine or azacitidine in relapsed or refractory AML under the ELN 2022 guidelines. We demonstrated that the ELN 2022 revision is not optimized for lower-intensity venetoclax-based strategies. To refine the prognostication schema, we showed significantly improved response and survival benefits for patients with mutated NPM1 and IDH. Relatively, patients with mutated NRAS, KRAS, and FLT3-ITD were associated with inferior response and survival. Furthermore, there is an unmet clinical need for tools to improve the selection of lower-intensity therapy candidates with borderline functional status. Using an incremental survival computation method, we discovered that a CCI score threshold of 5 distinguishes patients at an elevated risk of death. Together, these novel findings highlight areas of refinement to improve survival in relapsed or refractory AML.
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Affiliation(s)
- Ian M Bouligny
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Division of Hematology and Oncology, Department of Internal Medicine, Virginia Commonwealth University Massey Cancer Center, Richmond, VA, USA.
| | - Graeme Murray
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Michael Doyel
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Tilak Patel
- Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA, USA
| | - Josh Boron
- Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA, USA
| | - Valerie Tran
- Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA, USA
| | - Juhi Gor
- Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA, USA
| | - Yiwei Hang
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Yanal Alnimer
- Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA, USA
| | - Thuy Ho
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Kyle Zacholski
- Department of Pharmacy, Virginia Commonwealth University Medical Center, Richmond, VA, USA
| | - Chad Venn
- Department of Pharmacy, Virginia Commonwealth University Medical Center, Richmond, VA, USA
| | - Nolan A Wages
- Department of Biostatistics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Steven Grant
- Division of Hematology and Oncology, Department of Internal Medicine, Virginia Commonwealth University Massey Cancer Center, Richmond, VA, USA
| | - Keri R Maher
- Division of Hematology and Oncology, Department of Internal Medicine, Virginia Commonwealth University Massey Cancer Center, Richmond, VA, USA
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29
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Alyamany R, Alnughmush A, Almutlaq M, Alyamany M, Alfayez M. Azacitidine induced lung injury: report and contemporary discussion on diagnosis and management. Front Oncol 2024; 14:1345492. [PMID: 38406809 PMCID: PMC10884222 DOI: 10.3389/fonc.2024.1345492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 01/17/2024] [Indexed: 02/27/2024] Open
Abstract
Azacitidine, a hypomethylating agent, has caused a paradigm shift in the outcomes of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) who are not eligible for stem cell transplantation, particularly in combination with BCL2 and IDH inhibitors. Azacitidine and Azacitidine-based combinations have been widely considered a safe low-intensity therapy when compared to traditional conventional treatments. The development of lung toxicity from azacitidine is not a well-characterized adverse event. However, if it happens, it can be fatal, especially if not recognized and treated promptly. In this review, we aim to familiarize the reader with the presentation of azacitidine-induced lung injury, provide our suggested approach to management based on our experience and the current understanding of its mechanism, and review the literature of 20 case reports available on this topic.
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Affiliation(s)
- Ruah Alyamany
- Department of Hematology, Stem Cell Transplant and Cellular Therapy, Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ahmed Alnughmush
- Department of Hematology, Stem Cell Transplant and Cellular Therapy, Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Malak Almutlaq
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Mohammed Alyamany
- College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Mansour Alfayez
- Department of Hematology, Stem Cell Transplant and Cellular Therapy, Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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30
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Wu Y, Zehnle PMA, Rajak J, Koleci N, Andrieux G, Gallego-Villar L, Aumann K, Boerries M, Niemeyer CM, Flotho C, Bohler S, Erlacher M. BH3 mimetics and azacitidine show synergistic effects on juvenile myelomonocytic leukemia. Leukemia 2024; 38:136-148. [PMID: 37945692 PMCID: PMC10776398 DOI: 10.1038/s41375-023-02079-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 10/18/2023] [Accepted: 10/31/2023] [Indexed: 11/12/2023]
Abstract
Juvenile myelomonocytic leukemia (JMML) is an aggressive hematopoietic disorder of infancy and early childhood driven by constitutively active RAS signaling and characterized by abnormal proliferation of the granulocytic-monocytic blood cell lineage. Most JMML patients require hematopoietic stem cell transplantation for cure, but the risk of relapse is high for some JMML subtypes. Azacitidine was shown to effectively reduce leukemic burden in a subset of JMML patients. However, variable response rates to azacitidine and the risk of drug resistance highlight the need for novel therapeutic approaches. Since RAS signaling is known to interfere with the intrinsic apoptosis pathway, we combined various BH3 mimetic drugs with azacitidine in our previously established patient-derived xenograft model. We demonstrate that JMML cells require both MCL-1 and BCL-XL for survival, and that these proteins can be effectively targeted by azacitidine and BH3 mimetic combination treatment. In vivo azacitidine acts via downregulation of antiapoptotic MCL-1 and upregulation of proapoptotic BH3-only. The combination of azacitidine with BCL-XL inhibition was superior to BCL-2 inhibition in eliminating JMML cells. Our findings emphasize the need to develop clinically applicable MCL-1 or BCL-XL inhibitors in order to enable novel combination therapies in JMML refractory to standard therapy.
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Affiliation(s)
- Ying Wu
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
| | - Patricia M A Zehnle
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Jovana Rajak
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany
| | - Naile Koleci
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Geoffroy Andrieux
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Lorena Gallego-Villar
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Konrad Aumann
- University Medical Center Freiburg, Institute of Surgical Pathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Melanie Boerries
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg; and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Charlotte M Niemeyer
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Christian Flotho
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg; and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sheila Bohler
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Miriam Erlacher
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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Krauß L, Schneider C, Hessmann E, Saur D, Schneider G. Epigenetic control of pancreatic cancer metastasis. Cancer Metastasis Rev 2023; 42:1113-1131. [PMID: 37659057 PMCID: PMC10713713 DOI: 10.1007/s10555-023-10132-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 08/10/2023] [Indexed: 09/05/2023]
Abstract
Surgical resection, when combined with chemotherapy, has been shown to significantly improve the survival rate of patients with pancreatic ductal adenocarcinoma (PDAC). However, this treatment option is only feasible for a fraction of patients, as more than 50% of cases are diagnosed with metastasis. The multifaceted process of metastasis is still not fully understood, but recent data suggest that transcriptional and epigenetic plasticity play significant roles. Interfering with epigenetic reprogramming can potentially control the adaptive processes responsible for metastatic progression and therapy resistance, thereby enhancing treatment responses and preventing recurrence. This review will focus on the relevance of histone-modifying enzymes in pancreatic cancer, specifically on their impact on the metastatic cascade. Additionally, it will also provide a brief update on the current clinical developments in epigenetic therapies.
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Affiliation(s)
- Lukas Krauß
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.
| | - Carolin Schneider
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany
| | - Elisabeth Hessmann
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, 37075, Göttingen, Germany
- Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075, Göttingen, Germany
- CCC-N (Comprehensive Cancer Center Lower Saxony), 37075, Göttingen, Germany
| | - Dieter Saur
- Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, 81675, Munich, Germany
- German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany
| | - Günter Schneider
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.
- CCC-N (Comprehensive Cancer Center Lower Saxony), 37075, Göttingen, Germany.
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32
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Looi CK, Foong LC, Chung FFL, Khoo ASB, Loo EM, Leong CO, Mai CW. Targeting the crosstalk of epigenetic modifications and immune evasion in nasopharyngeal cancer. Cell Biol Toxicol 2023; 39:2501-2526. [PMID: 37755585 DOI: 10.1007/s10565-023-09830-9] [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: 07/13/2023] [Accepted: 09/11/2023] [Indexed: 09/28/2023]
Abstract
Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer that is highly associated with Epstein-Barr virus (EBV) infection. EBV acts as an epigenetic driver in NPC tumorigenesis, reprogramming the viral and host epigenomes to regulate viral latent gene expression, and creating an environment conducive to the malignant transformation of nasopharyngeal epithelial cells. Targeting epigenetic mechanisms in pre-clinical studies has been shown promise in eradicating tumours and overcoming immune resistance in some solid tumours. However, its efficacy in NPC remains inclusive due to the complex nature of this cancer. In this review, we provide an updated understanding of the roles of epigenetic factors in regulating EBV latent gene expression and promoting NPC progression. We also explore the crosstalk between epigenetic mechanisms and immune evasion in NPC. Particularly, we discuss the potential roles of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors in reversing immune suppression and augmenting antitumour immunity. Furthermore, we highlight the advantages of combining epigenetic therapy and immune checkpoint inhibitor to reverse immune resistance and improve clinical outcomes. Epigenetic drugs have the potential to modulate both epigenetic mediators and immune factors involved in NPC. However, further research is needed to fully comprehend the diverse range of epigenetic modifications in NPC. A deeper understanding of the crosstalk between epigenetic mechanisms and immune evasion during NPC progression is crucial for the development of more effective treatments for this challenging disease.
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Affiliation(s)
- Chin-King Looi
- School of Postgraduate Studies, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Lian-Chee Foong
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Pudong New District, Shanghai, 200127, China
| | - Felicia Fei-Lei Chung
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, 47500, Subang Jaya, Selangor, Malaysia
| | - Alan Soo-Beng Khoo
- School of Postgraduate Studies, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
- Department of Medical Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Pennsylvania, PA, 19107, USA
| | - Ee-Mun Loo
- AGTC Genomics, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, UCSI University, No. 1, Jalan Menara Gading, UCSI Heights, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Chee-Onn Leong
- AGTC Genomics, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
- Center for Cancer and Stem Cell Research, Development, and Innovation (IRDI), Institute for Research, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Chun-Wai Mai
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Pudong New District, Shanghai, 200127, China.
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, UCSI University, No. 1, Jalan Menara Gading, UCSI Heights, Cheras, 56000, Kuala Lumpur, Malaysia.
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Bouchla A, Papageorgiou SG, Symeonidis A, Sakellari I, Zikos P, Thomopoulos TP, Hatzimichael E, Galanopoulos A, Vyniou NA, Kotsianidis I, Pappa V. Evaluation of complete response to azacitidine according to the revised International Working Group 2023 response criteria for higher risk MDS. Does it make a difference in patients' outcome? Leukemia 2023; 37:2517-2519. [PMID: 37816955 PMCID: PMC10681887 DOI: 10.1038/s41375-023-02051-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/12/2023] [Accepted: 09/21/2023] [Indexed: 10/12/2023]
Affiliation(s)
- Anthi Bouchla
- Second Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Sotirios G Papageorgiou
- Second Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Argyris Symeonidis
- Department of Internal Medicine, University Hospital of Patras, Rio, Greece
| | - Ioanna Sakellari
- Department of Hematology and Stem cell Transplantation, Georgios Papanicolaou General Hospital, Thessaloniki, Greece
| | - Panagiotis Zikos
- Department of Hematology, Aghios Andreas General Hospital, Patras, Greece
| | - Thomas P Thomopoulos
- Second Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | | | | | | | - Ioannis Kotsianidis
- Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece
| | - Vasiliki Pappa
- Second Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece.
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Lee SW, Frankston CM, Kim J. Epigenome editing in cancer: Advances and challenges for potential therapeutic options. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 383:191-230. [PMID: 38359969 DOI: 10.1016/bs.ircmb.2023.10.001] [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: 02/17/2024]
Abstract
Cancers are diseases caused by genetic and non-genetic environmental factors. Epigenetic alterations, some attributed to non-genetic factors, can lead to cancer development. Epigenetic changes can occur in tumor suppressors or oncogenes, or they may contribute to global cell state changes, making cells abnormal. Recent advances in gene editing technology show potential for cancer treatment. Herein, we will discuss our current knowledge of epigenetic alterations occurring in cancer and epigenetic editing technologies that can be applied to developing therapeutic options.
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Affiliation(s)
- Seung-Won Lee
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States; Department of Molecular and Medical Genetics, School of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - Connor Mitchell Frankston
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States; Biomedical Engineering Graduate Program, Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - Jungsun Kim
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States; Department of Molecular and Medical Genetics, School of Medicine, Oregon Health & Science University, Portland, OR, United States; Cancer Biology Research Program, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States.
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Shah R, Spektor TM, Weisenberger DJ, Ding H, Patil R, Amador C, Song XY, Chun ST, Inzalaco J, Turjman S, Ghiam S, Jeong-Kim J, Tolstoff S, Yampolsky SV, Sawant OB, Rabinowitz YS, Maguen E, Hamrah P, Svendsen CN, Saghizadeh M, Ljubimova JY, Kramerov AA, Ljubimov AV. Reversal of dual epigenetic repression of non-canonical Wnt-5a normalises diabetic corneal epithelial wound healing and stem cells. Diabetologia 2023; 66:1943-1958. [PMID: 37460827 PMCID: PMC10474199 DOI: 10.1007/s00125-023-05960-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 05/18/2023] [Indexed: 09/02/2023]
Abstract
AIMS/HYPOTHESIS Diabetes is associated with epigenetic modifications including DNA methylation and miRNA changes. Diabetic complications in the cornea can cause persistent epithelial defects and impaired wound healing due to limbal epithelial stem cell (LESC) dysfunction. In this study, we aimed to uncover epigenetic alterations in diabetic vs non-diabetic human limbal epithelial cells (LEC) enriched in LESC and identify new diabetic markers that can be targeted for therapy to normalise corneal epithelial wound healing and stem cell expression. METHODS Human LEC were isolated, or organ-cultured corneas were obtained, from autopsy eyes from non-diabetic (59.87±20.89 years) and diabetic (71.93±9.29 years) donors. The groups were not statistically different in age. DNA was extracted from LEC for methylation analysis using Illumina Infinium 850K MethylationEPIC BeadChip and protein was extracted for Wnt phospho array analysis. Wound healing was studied using a scratch assay in LEC or 1-heptanol wounds in organ-cultured corneas. Organ-cultured corneas and LEC were transfected with WNT5A siRNA, miR-203a mimic or miR-203a inhibitor or were treated with recombinant Wnt-5a (200 ng/ml), DNA methylation inhibitor zebularine (1-20 µmol/l) or biodegradable nanobioconjugates (NBCs) based on polymalic acid scaffold containing antisense oligonucleotide (AON) to miR-203a or a control scrambled AON (15-20 µmol/l). RESULTS There was significant differential DNA methylation between diabetic and non-diabetic LEC. WNT5A promoter was hypermethylated in diabetic LEC accompanied with markedly decreased Wnt-5a protein. Treatment of diabetic LEC and organ-cultured corneas with exogenous Wnt-5a accelerated wound healing by 1.4-fold (p<0.05) and 37% (p<0.05), respectively, and increased LESC and diabetic marker expression. Wnt-5a treatment in diabetic LEC increased the phosphorylation of members of the Ca2+-dependent non-canonical pathway (phospholipase Cγ1 and protein kinase Cβ; by 1.15-fold [p<0.05] and 1.36-fold [p<0.05], respectively). In diabetic LEC, zebularine treatment increased the levels of Wnt-5a by 1.37-fold (p<0.01)and stimulated wound healing in a dose-dependent manner with a 1.6-fold (p<0.01) increase by 24 h. Moreover, zebularine also improved wound healing by 30% (p<0.01) in diabetic organ-cultured corneas and increased LESC and diabetic marker expression. Transfection of these cells with WNT5A siRNA abrogated wound healing stimulation by zebularine, suggesting that its effect was primarily due to inhibition of WNT5A hypermethylation. Treatment of diabetic LEC and organ-cultured corneas with NBC enhanced wound healing by 1.4-fold (p<0.01) and 23.3% (p<0.05), respectively, with increased expression of LESC and diabetic markers. CONCLUSIONS/INTERPRETATION We provide the first account of epigenetic changes in diabetic corneas including dual inhibition of WNT5A by DNA methylation and miRNA action. Overall, Wnt-5a is a new corneal epithelial wound healing stimulator that can be targeted to improve wound healing and stem cells in the diabetic cornea. DATA AVAILABILITY The DNA methylation dataset is available from the public GEO repository under accession no. GSE229328 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE229328 ).
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Affiliation(s)
- Ruchi Shah
- Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| | - Tanya M Spektor
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Kura Oncology, Inc., Boston, MA, USA
| | | | - Hui Ding
- Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Kunshan Xinyunda Biotech Co., Ltd., Kunshan, China
| | - Rameshwar Patil
- Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Basic Science, Division of Cancer Science, Loma Linda University Cancer Center, Loma Linda, CA, USA
| | - Cynthia Amador
- Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Xue-Ying Song
- Applied Genomics, Computation, and Translational Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Steven T Chun
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- University of California Los Angeles, Los Angeles, CA, USA
| | - Jake Inzalaco
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- University of California Los Angeles, Los Angeles, CA, USA
| | - Sue Turjman
- Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Mount Saint Mary's University, Los Angeles, CA, USA
| | - Sean Ghiam
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Sackler School of Medicine, New York State/American Program of Tel Aviv University, Tel Aviv, Israel
| | - Jiho Jeong-Kim
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- University of California Los Angeles, Los Angeles, CA, USA
| | - Sasha Tolstoff
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- California Institute of Technology, Pasadena, CA, USA
| | - Sabina V Yampolsky
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Duke University, Durham, NC, USA
| | - Onkar B Sawant
- Center for Vision and Eye Banking Research, Eversight, Cleveland, OH, USA
| | - Yaron S Rabinowitz
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ezra Maguen
- American Eye Institute, Los Angeles, CA, USA
| | - Pedram Hamrah
- Cornea Service, New England Eye Center, Tufts Medical Center, Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, USA
| | - Clive N Svendsen
- Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Mehrnoosh Saghizadeh
- Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Julia Y Ljubimova
- Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Terasaki Institute for Biomedical Innovation, Los Angeles, CA, USA
| | - Andrei A Kramerov
- Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Alexander V Ljubimov
- Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
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Yang J, Zhang L, Qiao W, Luo Y. Mycobacterium tuberculosis: Pathogenesis and therapeutic targets. MedComm (Beijing) 2023; 4:e353. [PMID: 37674971 PMCID: PMC10477518 DOI: 10.1002/mco2.353] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 07/31/2023] [Accepted: 08/03/2023] [Indexed: 09/08/2023] Open
Abstract
Tuberculosis (TB) remains a significant public health concern in the 21st century, especially due to drug resistance, coinfection with diseases like immunodeficiency syndrome (AIDS) and coronavirus disease 2019, and the lengthy and costly treatment protocols. In this review, we summarize the pathogenesis of TB infection, therapeutic targets, and corresponding modulators, including first-line medications, current clinical trial drugs and molecules in preclinical assessment. Understanding the mechanisms of Mycobacterium tuberculosis (Mtb) infection and important biological targets can lead to innovative treatments. While most antitubercular agents target pathogen-related processes, host-directed therapy (HDT) modalities addressing immune defense, survival mechanisms, and immunopathology also hold promise. Mtb's adaptation to the human host involves manipulating host cellular mechanisms, and HDT aims to disrupt this manipulation to enhance treatment effectiveness. Our review provides valuable insights for future anti-TB drug development efforts.
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Affiliation(s)
- Jiaxing Yang
- Center of Infectious Diseases and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Laiying Zhang
- Center of Infectious Diseases and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Wenliang Qiao
- Department of Thoracic Surgery, West China HospitalSichuan UniversityChengduSichuanChina
- Lung Cancer Center, West China HospitalSichuan UniversityChengduSichuanChina
| | - Youfu Luo
- Center of Infectious Diseases and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
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Akagi Y, Yamashita Y, Kosako H, Furuya Y, Hosoi H, Mushino T, Murata S, Nishikawa A, Tamura S, Nakao T, Sonoki T. Administration of combined venetoclax and azacitidine in a patient with acute myeloid leukemia and multiple comorbidities undergoing dialysis: A case report. EJHAEM 2023; 4:841-843. [PMID: 37601888 PMCID: PMC10435694 DOI: 10.1002/jha2.732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/26/2023] [Accepted: 05/31/2023] [Indexed: 08/22/2023]
Abstract
Patients with acute myeloid leukemia (AML) who have comorbidities have limited treatment options, thereby resulting in poor prognosis. Venetoclax, a specific B-cell lymphoma-2 inhibitor, has recently been approved for AML in combination with hypomethylating agents; however, only one report has described its use in patients undergoing dialysis. Herein, we report the effectiveness of combined venetoclax and azacitidine in a 73-year-old man with AML undergoing dialysis and who was ineligible for standard therapies. The safety of venetoclax and azacitidine in patients undergoing dialysis has been reported, and their combination may be a feasible option for patients with AML undergoing dialysis.
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Affiliation(s)
- Yuina Akagi
- Department of Hematology/OncologyWakayama Medical UniversityWakayamaJapan
- Department of HematologyNaga Municipal HospitalWakayamaJapan
| | - Yusuke Yamashita
- Department of Hematology/OncologyWakayama Medical UniversityWakayamaJapan
- Department of HematologyNaga Municipal HospitalWakayamaJapan
| | - Hideki Kosako
- Department of Hematology/OncologyWakayama Medical UniversityWakayamaJapan
| | - Yoshiaki Furuya
- Department of Hematology/OncologyWakayama Medical UniversityWakayamaJapan
- Department of HematologyNaga Municipal HospitalWakayamaJapan
| | - Hiroki Hosoi
- Department of Hematology/OncologyWakayama Medical UniversityWakayamaJapan
| | - Toshiki Mushino
- Department of Hematology/OncologyWakayama Medical UniversityWakayamaJapan
| | - Shogo Murata
- Department of Hematology/OncologyWakayama Medical UniversityWakayamaJapan
| | - Akinori Nishikawa
- Department of Hematology/OncologyWakayama Medical UniversityWakayamaJapan
| | - Shinobu Tamura
- Department of Hematology/OncologyWakayama Medical UniversityWakayamaJapan
| | - Taisei Nakao
- Department of HematologyNaga Municipal HospitalWakayamaJapan
- Department of Internal MedicineNaga Municipal HospitalWakayamaJapan
| | - Takashi Sonoki
- Department of Hematology/OncologyWakayama Medical UniversityWakayamaJapan
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Zheng Q, Wang H, Yan A, Yin F, Qiao X. DNA Methylation in Alcohol Use Disorder. Int J Mol Sci 2023; 24:10130. [PMID: 37373281 DOI: 10.3390/ijms241210130] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/10/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Excessive drinking damages the central nervous system of individuals and can even cause alcohol use disorder (AUD). AUD is regulated by both genetic and environmental factors. Genes determine susceptibility to alcohol, and the dysregulation of epigenome drives the abnormal transcription program and promotes the occurrence and development of AUD. DNA methylation is one of the earliest and most widely studied epigenetic mechanisms that can be inherited stably. In ontogeny, DNA methylation pattern is a dynamic process, showing differences and characteristics at different stages. DNA dysmethylation is prevalent in human cancer and alcohol-related psychiatric disorders, resulting in local hypermethylation and transcriptional silencing of related genes. Here, we summarize recent findings on the roles and regulatory mechanisms of DNA methylation, the development of methyltransferase inhibitors, methylation alteration during alcohol exposure at different stages of life, and possible therapeutic options for targeting methylation in human and animal studies.
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Affiliation(s)
- Qingmeng Zheng
- Department of Pathology and Forensic Medicine, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Heng Wang
- Department of Pathology and Forensic Medicine, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - An Yan
- Department of Pathology and Forensic Medicine, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Fangyuan Yin
- School of Medicine, College of Forensic Science, Xi'an Jiaotong University, Xi'an 710061, China
| | - Xiaomeng Qiao
- Department of Pathology and Forensic Medicine, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
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Sorrentino C, Di Carlo E. Molecular Targeted Therapies in Metastatic Prostate Cancer: Recent Advances and Future Challenges. Cancers (Basel) 2023; 15:2885. [PMID: 37296848 PMCID: PMC10251915 DOI: 10.3390/cancers15112885] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 05/19/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
Prostate cancer is the most frequent malignant tumor in men, and, despite the great improvements in survival in patients with localized cancer, the prognosis for metastatic disease remains poor. Novel molecular targeted therapies, which block specific molecules or signaling pathways in tumor cells or in their microenvironment, have shown encouraging results in metastatic castration-resistant prostate cancer. Among these therapeutic approaches, prostate-specific membrane antigen-targeted radionuclide therapies and DNA repair inhibitors represent the most promising ones, with some therapeutic protocols already approved by the FDA, whereas therapies targeting tumor neovascularization and immune checkpoint inhibitors have not yet demonstrated clear clinical benefits. In this review, the most relevant studies and clinical trials on this topic are illustrated and discussed, together with future research directions and challenges.
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Affiliation(s)
- Carlo Sorrentino
- Department of Medicine and Sciences of Aging, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy;
- Anatomic Pathology and Immuno-Oncology Unit, Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Emma Di Carlo
- Department of Medicine and Sciences of Aging, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy;
- Anatomic Pathology and Immuno-Oncology Unit, Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
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40
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Nickel GA, Diehl KL. Chemical Biology Approaches to Identify and Profile Interactors of Chromatin Modifications. ACS Chem Biol 2023; 18:1014-1026. [PMID: 35238546 PMCID: PMC9440160 DOI: 10.1021/acschembio.1c00794] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
In eukaryotes, DNA is packaged with histone proteins in a complex known as chromatin. Both the DNA and histone components of chromatin can be chemically modified in a wide variety of ways, resulting in a complex landscape often referred to as the "epigenetic code". These modifications are recognized by effector proteins that remodel chromatin and modulate transcription, translation, and repair of the underlying DNA. In this Review, we examine the development of methods for characterizing proteins that interact with these histone and DNA modifications. "Mark first" approaches utilize chemical, peptide, nucleosome, or oligonucleotide probes to discover interactors of a specific modification. "Reader first" approaches employ arrays of peptides, nucleosomes, or oligonucleotides to profile the binding preferences of interactors. These complementary strategies have greatly enhanced our understanding of how chromatin modifications effect changes in genomic regulation, bringing us ever closer to deciphering this complex language.
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Affiliation(s)
- Garrison A. Nickel
- Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, United States
| | - Katharine L. Diehl
- Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, United States
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41
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Lin C, Liu P, Shi C, Qiu L, Shang D, Lu Z, Tu Z, Liu H. Therapeutic targeting of DNA damage repair pathways guided by homologous recombination deficiency scoring in ovarian cancers. Fundam Clin Pharmacol 2023; 37:194-214. [PMID: 36130021 DOI: 10.1111/fcp.12834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 07/23/2022] [Accepted: 09/20/2022] [Indexed: 12/01/2022]
Abstract
The susceptibility of cells to DNA damage and their DNA repair ability are crucial for cancer therapy. Homologous recombination is one of the major repairing mechanisms for DNA double-strand breaks. Approximately half of ovarian cancer (OvCa) cells harbor homologous recombination deficiency (HRD). Considering that HRD is a major hallmark of OvCas, scholars proposed HRD scoring to evaluate the HRD degree and guide the choice of therapeutic strategies for OvCas. In the last decade, synthetic lethal strategy by targeting poly (ADP-ribose) polymerase (PARP) in HR-deficient OvCas has attracted considerable attention in view of its favorable clinical effort. We therefore suggested that the uses of other DNA damage/repair-targeted drugs in HR-deficient OvCas might also offer better clinical outcome. Here, we reviewed the current small molecule compounds that targeted DNA damage/repair pathways and discussed the HRD scoring system to guide their clinical uses.
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Affiliation(s)
- Chunxiu Lin
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Peng Liu
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Chaowen Shi
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Lipeng Qiu
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Dongsheng Shang
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Ziwen Lu
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Zhigang Tu
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Hanqing Liu
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China
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42
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Alpoim-Moreira J, Szóstek-Mioduchowska A, Słyszewska M, Rebordão MR, Skarzynski DJ, Ferreira-Dias G. 5-Aza-2′-Deoxycytidine (5-Aza-dC, Decitabine) Inhibits Collagen Type I and III Expression in TGF-β1-Treated Equine Endometrial Fibroblasts. Animals (Basel) 2023; 13:ani13071212. [PMID: 37048467 PMCID: PMC10093662 DOI: 10.3390/ani13071212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/03/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
Endometrosis negatively affects endometrial function and fertility in mares, due to excessive deposition of type I (COL1) and type III (COL3) collagens. The pro-fibrotic transforming growth factor (TGF-β1) induces myofibroblast differentiation, characterized by α-smooth muscle actin (α-SMA) expression, and collagen synthesis. In humans, fibrosis has been linked to epigenetic mechanisms. To the best of our knowledge, this has not been described in mare endometrium. Therefore, this study aimed to investigate the in vitro epigenetic regulation in TGF-β1-treated mare endometrial fibroblasts and the use of 5-aza-2′-deoxycytidine (5-aza-dC), an epigenetic modifier, as a putative treatment option for endometrial fibrosis. Methods and Results: The in vitro effects of TGF-β1 and of 5-aza-dC on DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B), COL1A1, COL3A1, and α-SMA transcripts were analyzed in endometrial fibroblasts, and COL1 and COL3 secretion in a co-culture medium. TGF-β1 upregulated DNMT3A transcripts and collagen secretion. In TGF-β1-treated endometrial fibroblasts, DNA methylation inhibitor 5-aza-dC decreased collagen transcripts and secretion, but not α-SMA transcripts. Conclusion: These findings suggest a possible role of epigenetic mechanisms during equine endometrial fibrogenesis. The in vitro effect of 5-aza-dC on collagen reduction in TGF-β1-treated fibroblasts highlights this epigenetic involvement. This may pave the way to different therapeutic approaches for endometrosis.
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43
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Cheon H, Hur JK, Hwang W, Yang HJ, Son JH. Epigenetic modification of gene expression in cancer cells by terahertz demethylation. Sci Rep 2023; 13:4930. [PMID: 36967404 PMCID: PMC10040409 DOI: 10.1038/s41598-023-31828-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/17/2023] [Indexed: 03/29/2023] Open
Abstract
Terahertz (THz) radiation can affect the degree of DNA methylation, the spectral characteristics of which exist in the terahertz region. DNA methylation is an epigenetic modification in which a methyl (CH3) group is attached to cytosine, a nucleobase in human DNA. Appropriately controlled DNA methylation leads to proper regulation of gene expression. However, abnormal gene expression that departs from controlled genetic transcription through aberrant DNA methylation may occur in cancer or other diseases. In this study, we demonstrate the modification of gene expression in cells by THz demethylation using resonant THz radiation. Using an enzyme-linked immunosorbent assay, we observed changes in the degree of global DNA methylation in the SK-MEL-3 melanoma cell line under irradiation with 1.6-THz radiation with limited spectral bandwidth. Resonant THz radiation demethylated living melanoma cells by 19%, with no significant occurrence of apurinic/apyrimidinic sites, and the demethylation ratio was linearly proportional to the power of THz radiation. THz demethylation downregulates FOS, JUN, and CXCL8 genes, which are involved in cancer and apoptosis pathways. Our results show that THz demethylation has the potential to be a gene expression modifier with promising applications in cancer treatment.
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Affiliation(s)
- Hwayeong Cheon
- Biomedical Engineering Research Center, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Junho K Hur
- Department of Genetics, College of Medicine, Graduate School of Biomedical Sciences and Engineering, Hanyang University, Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea
| | - Woochang Hwang
- Department of Pre-Medicine, College of Medicine, Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea
| | - Hee-Jin Yang
- Department of Neurosurgery, Seoul National University Boramae Medical Center, 20 Boramae-ro 5-gil, Dognjak-gu, Seoul, 07061, Republic of Korea.
| | - Joo-Hiuk Son
- Department of Physics, University of Seoul, 163, Seoulsiripdae-ro, Dongdaemun-gu, Seoul, 02504, Republic of Korea.
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44
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Kang L, Zhang H, Jia C, Zhang R, Shen C. Epigenetic modifications of inflammation in intervertebral disc degeneration. Ageing Res Rev 2023; 87:101902. [PMID: 36871778 DOI: 10.1016/j.arr.2023.101902] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 02/17/2023] [Accepted: 03/02/2023] [Indexed: 03/07/2023]
Abstract
Intervertebral disc degeneration (IDD) is a common cause of joint-related chronic disability in elderly individuals worldwide. It seriously impacts the quality of life and inflicts a substantial social and economic burden. The pathological mechanisms underlying IDD have not been fully revealed, leading to less satisfactory clinical treatment outcomes. More studies are urgently needed to reveal its precise pathological mechanisms. Numerous studies have revealed that inflammation is closely related to various pathological processes of IDD, including the continuous loss of extracellular matrix, cell apoptosis, and senescence, indicating the important role of inflammation in the pathological mechanism of IDD. Epigenetic modifications affect the functions and characteristics of genes mainly through DNA methylation, histone modification, non-coding RNA regulation, and other mechanisms, thus having a major effect on the survival state of the body. Recently, the role of epigenetic modifications in inflammation during IDD has been attracting research interest. In this review, we summarize the roles of different types of epigenetic modifications in inflammation during IDD in recent years, to improve our understanding of the etiology of IDD and to transform basic research strategy into a clinically effective treatment for joint-related chronic disability in elderly individuals.
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Affiliation(s)
- Liang Kang
- Department of Orthopedics & Spine Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Huaqing Zhang
- Department of Orthopedics & Spine Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Chongyu Jia
- Department of Orthopedics & Spine Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Renjie Zhang
- Department of Orthopedics & Spine Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
| | - Cailiang Shen
- Department of Orthopedics & Spine Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
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45
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Toward the Development of Epigenome Editing-Based Therapeutics: Potentials and Challenges. Int J Mol Sci 2023; 24:ijms24054778. [PMID: 36902207 PMCID: PMC10003136 DOI: 10.3390/ijms24054778] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/27/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
The advancement in epigenetics research over the past several decades has led to the potential application of epigenome-editing technologies for the treatment of various diseases. In particular, epigenome editing is potentially useful in the treatment of genetic and other related diseases, including rare imprinted diseases, as it can regulate the expression of the epigenome of the target region, and thereby the causative gene, with minimal or no modification of the genomic DNA. Various efforts are underway to successfully apply epigenome editing in vivo, such as improving target specificity, enzymatic activity, and drug delivery for the development of reliable therapeutics. In this review, we introduce the latest findings, summarize the current limitations and future challenges in the practical application of epigenome editing for disease therapy, and introduce important factors to consider, such as chromatin plasticity, for a more effective epigenome editing-based therapy.
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46
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Zeidan AM, Giagounidis A, Sekeres MA, Xiao Z, Sanz GF, Hoef MV, Ma F, Hertle S, Santini V. STIMULUS-MDS2 design and rationale: a phase III trial with the anti-TIM-3 sabatolimab (MBG453) + azacitidine in higher risk MDS and CMML-2. Future Oncol 2023; 19:631-642. [PMID: 37083373 DOI: 10.2217/fon-2022-1237] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/22/2023] Open
Abstract
Patients with higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) unfit for hematopoietic stem cell transplantation have poor outcomes. Novel therapies that provide durable benefit with favorable tolerability and clinically meaningful improvement in survival are needed. T-cell immunoglobulin domain and mucin domain-3 (TIM-3) is an immuno-myeloid regulator expressed on immune and leukemic stem cells in myeloid malignancies. Sabatolimab is a novel immunotherapy targeting TIM-3 with a potential dual mechanism of reactivating the immune system and directly targeting TIM-3+ leukemic blasts suppressing the growth of cancer cells. Here, we describe the aims and design of the phase III STIMULUS-MDS2 trial, which aims to demonstrate the potential for sabatolimab plus azacitidine to improve survival for patients with higher-risk MDS and CMML-2 (NCT04266301). Clinical Trial Registration: NCT04266301 (ClinicalTrials.gov).
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Affiliation(s)
- Amer M Zeidan
- Yale University & Yale Cancer Center, New Haven, CT 06510, USA
| | | | - Mikkael A Sekeres
- Division of Hematology, Sylvester Cancer Center, University of Miami, Miami, FL 33065, USA
| | - Zhijian Xiao
- Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, 300020, China
| | - Guillermo F Sanz
- Hospital Universitario y Politécnico La Fe, Valencia, 46026, Spain
- Health Research Institute La Fe (IIS La Fe), Valencia, 46026, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, 28029, Spain
| | | | - Fei Ma
- Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA
| | | | - Valeria Santini
- MDS Unit, Hematology, University of Florence, Florence, 50121, Italy
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47
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Kinnel B, Singh SK, Oprea-Ilies G, Singh R. Targeted Therapy and Mechanisms of Drug Resistance in Breast Cancer. Cancers (Basel) 2023; 15:1320. [PMID: 36831661 PMCID: PMC9954028 DOI: 10.3390/cancers15041320] [Citation(s) in RCA: 62] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/15/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Breast cancer is the most common cause of cancer-related death in women worldwide. Multidrug resistance (MDR) has been a large hurdle in reducing BC death rates. The drug resistance mechanisms include increased drug efflux, enhanced DNA repair, senescence escape, epigenetic alterations, tumor heterogeneity, tumor microenvironment (TME), and the epithelial-to-mesenchymal transition (EMT), which make it challenging to overcome. This review aims to explain the mechanisms of resistance in BC further, identify viable drug targets, and elucidate how those targets relate to the progression of BC and drug resistance.
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Affiliation(s)
- Briana Kinnel
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Santosh Kumar Singh
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Gabriela Oprea-Ilies
- Department of Pathology & Laboratory Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Rajesh Singh
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA
- Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA
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48
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Zhao A, Zhou H, Yang J, Li M, Niu T. Epigenetic regulation in hematopoiesis and its implications in the targeted therapy of hematologic malignancies. Signal Transduct Target Ther 2023; 8:71. [PMID: 36797244 PMCID: PMC9935927 DOI: 10.1038/s41392-023-01342-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 01/03/2023] [Accepted: 01/19/2023] [Indexed: 02/18/2023] Open
Abstract
Hematologic malignancies are one of the most common cancers, and the incidence has been rising in recent decades. The clinical and molecular features of hematologic malignancies are highly heterogenous, and some hematologic malignancies are incurable, challenging the treatment, and prognosis of the patients. However, hematopoiesis and oncogenesis of hematologic malignancies are profoundly affected by epigenetic regulation. Studies have found that methylation-related mutations, abnormal methylation profiles of DNA, and abnormal histone deacetylase expression are recurrent in leukemia and lymphoma. Furthermore, the hypomethylating agents and histone deacetylase inhibitors are effective to treat acute myeloid leukemia and T-cell lymphomas, indicating that epigenetic regulation is indispensable to hematologic oncogenesis. Epigenetic regulation mainly includes DNA modifications, histone modifications, and noncoding RNA-mediated targeting, and regulates various DNA-based processes. This review presents the role of writers, readers, and erasers of DNA methylation and histone methylation, and acetylation in hematologic malignancies. In addition, this review provides the influence of microRNAs and long noncoding RNAs on hematologic malignancies. Furthermore, the implication of epigenetic regulation in targeted treatment is discussed. This review comprehensively presents the change and function of each epigenetic regulator in normal and oncogenic hematopoiesis and provides innovative epigenetic-targeted treatment in clinical practice.
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Affiliation(s)
- Ailin Zhao
- Department of Hematology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Hui Zhou
- Department of Hematology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Jinrong Yang
- Department of Hematology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Meng Li
- Department of Hematology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Ting Niu
- Department of Hematology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China.
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49
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Klein SO, Baniahmad AA, Jung M. Photoreductive β-aminoalkylation with amino acids affords functionalized γ-aminoketones for nucleoside mimics. Chem Commun (Camb) 2023; 59:1971-1974. [PMID: 36722995 DOI: 10.1039/d2cc06071j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We developed a facile photoreductive and stereoselective β-aminoalkylation of a crowded enone by blue LED light irradiation using a wide variety of α-amino acids in order to access 5'-amino substituted carbasugar nucleosides for SAM-based methyltransferase inhibitors. This photochemical method provides highly functionalized carbasugar mimics for nucleoside analogue synthesis.
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Affiliation(s)
- Sebastian O Klein
- Institute of Pharmaceutical Sciences, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany. .,CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Germany
| | - Adina A Baniahmad
- Institute of Pharmaceutical Sciences, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany.
| | - Manfred Jung
- Institute of Pharmaceutical Sciences, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany. .,CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Germany
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50
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Zhang Z, Wang G, Li Y, Lei D, Xiang J, Ouyang L, Wang Y, Yang J. Recent progress in DNA methyltransferase inhibitors as anticancer agents. Front Pharmacol 2022; 13:1072651. [PMID: 37077808 PMCID: PMC10107375 DOI: 10.3389/fphar.2022.1072651] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022] Open
Abstract
DNA methylation mediated by DNA methyltransferase is an important epigenetic process that regulates gene expression in mammals, which plays a key role in silencing certain genes, such as tumor suppressor genes, in cancer, and it has become a promising therapeutic target for cancer treatment. Similar to other epigenetic targets, DNA methyltransferase can also be modulated by chemical agents. Four agents have already been approved to treat hematological cancers. In order to promote the development of a DNA methyltransferase inhibitor as an anti-tumor agent, in the current review, we discuss the relationship between DNA methylation and tumor, the anti-tumor mechanism, the research progress and pharmacological properties of DNA methyltransferase inhibitors, and the future research trend of DNA methyltransferase inhibitors.
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Affiliation(s)
- Zhixiong Zhang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, Innovation Center of Nursing Research, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Guan Wang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, Innovation Center of Nursing Research, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
| | - Yuyan Li
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, Innovation Center of Nursing Research, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Dongsheng Lei
- School of Physical Science and Technology, Electron Microscopy Center of Lanzhou University, Lanzhou University, Lanzhou, China
| | - Jin Xiang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, Innovation Center of Nursing Research, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
| | - Liang Ouyang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, Innovation Center of Nursing Research, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
- Science and Technology Department, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Yanyan Wang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, Innovation Center of Nursing Research, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
- Science and Technology Department, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Yanyan Wang, ; Jinliang Yang,
| | - Jinliang Yang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, Innovation Center of Nursing Research, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
- *Correspondence: Yanyan Wang, ; Jinliang Yang,
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