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Cho J, Bejaoui M, Isoda H. Regulation of keratinocyte proliferation and differentiation by secoiridoid oleacein in monoculture and fibroblast co-culture models. Biomed Pharmacother 2025; 185:117985. [PMID: 40088777 DOI: 10.1016/j.biopha.2025.117985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/04/2025] [Accepted: 03/10/2025] [Indexed: 03/17/2025] Open
Abstract
Aberrant differentiation of keratinocytes is closely associated with both pathological skin disorders and non-pathological skin conditions, making the maintenance of normal differentiation process essential for skin integrity and homeostasis. This study investigated the effect of olive-derived secoiridoid oleacein (OC) on keratinocyte proliferation and differentiation in vitro and further validated it in a co-culture model with fibroblasts mimicking a skin-like environment. OC was compared with oleuropein (OP) as a reference compound having similar chemical structure and reported effects on skin barrier formation and wound healing. Notably, OC significantly increased the proliferation makers KRT5 and KRT14 and demonstrated wound healing effect under low-calcium condition, reflecting characteristics of the basal layer. Under high-calcium condition, OC markedly upregulated differentiation markers KRT10, IVL, FLG, and TGM1, along with differentiation characteristics such as cytoplasmic extensions and cell adhesion. Transcriptomic analysis revealed that OP and OC shared a common upstream pathway, Integrin/E-cadherin-Rho-MAPK, at the cytoplasm, while they showed distinct regulatory mechanisms within the nucleus. OP induced differentiation by suppressing stemness genes through epigenetic regulation, whereas OC secured differentiation stability by suppressing proliferative gene ESR1 and activating the DNA damage response from DNA damage or mechanical stress occurring during differentiation. Our study is the first to elucidate the dual regulatory effects of OC on keratinocyte proliferation and differentiation stage-dependently as well as its underlying molecular mechanisms, suggesting that the divergent regulatory mechanisms may be due to their structural differences. These findings highlight OC as a skin protective agent for maintaining skin health and suggest its therapeutic potential for skin disorders related to abnormal differentiation.
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Affiliation(s)
- Juhee Cho
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba 305-0006, Japan
| | - Meriem Bejaoui
- Open Innovation Laboratory for Food and Medicinal Resource Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8577, Japan
| | - Hiroko Isoda
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba 305-0006, Japan; Open Innovation Laboratory for Food and Medicinal Resource Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8577, Japan; Institute of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8577, Japan.
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Ma J, Zhang Y, Li J, Dang Y, Hu D. Regulation of histone H3K27 methylation in inflammation and cancer. MOLECULAR BIOMEDICINE 2025; 6:14. [PMID: 40042761 PMCID: PMC11882493 DOI: 10.1186/s43556-025-00254-x] [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: 08/26/2024] [Revised: 02/17/2025] [Accepted: 02/19/2025] [Indexed: 03/09/2025] Open
Abstract
Inflammation is a multifaceted defense mechanism of the immune system against infection. Chronic inflammation is intricately linked to all stages of tumorigenesis and is therefore associated with an elevated risk of developing serious cancers. Epigenetic mechanisms have the capacity to trigger inflammation as well as facilitate tumor development and transformation within an inflammatory context. They achieve this by dynamically modulating the expression of both pro-inflammatory and anti-inflammatory cytokines, which in turn sustains chronic inflammation. The aberrant epigenetic landscape reconfigures the transcriptional programs of inflammatory and oncogenic genes. This reconfiguration is pivotal in dictating the biological functions of both tumor cells and immune cells. Aberrant histone H3 lysine 27 site (H3K27) methylation has been shown to be involved in biological behaviors such as inflammation development, tumor progression, and immune response. The establishment and maintenance of this repressive epigenetic mark is dependent on the involvement of the responsible histone modifying enzymes enhancer of zeste homologue 2 (EZH2), jumonji domain containing 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat gene X (UTX) as well as multiple cofactors. In addition, specific pharmacological agents have been shown to modulate H3K27 methylation levels, thereby modulating inflammation and carcinogenesis. This review comprehensively summarises the current characteristics and clinical significance of epigenetic regulation of H3K27 methylation in the context of inflammatory response and tumor progression.
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Affiliation(s)
- Jing Ma
- Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong New Area, Shanghai, 200137, China
| | - Yalin Zhang
- Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong New Area, Shanghai, 200137, China
| | - Jingyuan Li
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, (Shanghai University of Traditional Chinese Medicine), Shanghai, 200032, China
| | - Yanqi Dang
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, (Shanghai University of Traditional Chinese Medicine), Shanghai, 200032, China.
| | - Dan Hu
- Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong New Area, Shanghai, 200137, China.
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Dasi S, Naab TJ, Kwabi-Addo B, Apprey V, Beyene D, Dewitty RL, Nagel S, Williams R, Bolden K, Hayes-Dixon A, Shokrani B, Stewart DA, Kassim OO, Copeland RL, Kanaan YM. Methylation of ESRα Promoters in Benign Breast Tumors Could Be a Signature for Progression to Breast Cancer in African American Women. Cancer Genomics Proteomics 2025; 22:208-230. [PMID: 39993808 PMCID: PMC11880923 DOI: 10.21873/cgp.20497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 01/20/2025] [Accepted: 01/22/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND/AIM Methylation in the estrogen receptor alpha (ESRα) promoter is an epigenetic abnormality associated with breast cancer (BCa), whereas hypermethylation results in the loss of ER expression. MATERIALS AND METHODS Pyrosequencing was used to investigate a potential link between aberrant methylation in the P0/P1 promoters of ESRα and the risk of progression of benign fibrocystic and fibroadenoma tumors to BCa. RESULTS Results showed a significantly elevated level of DNA methylation in ESRα P1 promoter (p=0.0001) in fibroadenoma compared to ER-negative BCa tumors and a two-fold increased ESRα expression in fibrocystic and fibroadenoma benign tissues. In addition, methylation levels of HIN-1 and RASSF1A promoters were elevated in ER-positive compared to ER-negative BCa (p-value<0.04). ANOVA Mixed Model revealed significantly higher methylation levels in the promoter of RASSF1A for fibroadenoma and ER-positive BCa (p=0.004) compared to ER-negative BCa. Tumors with unclassified molecular subtypes (ER-positive, PR-negative, HER2-negative) had elevated levels of methylation (p=0.046) in the P0 promoter compared with luminal B (ER-positive, PR-positive, HER2-positive) tumors. Grade 3 tumors showed a borderline association with ESRα P1 promoter methylation when compared with grade 2 tumors (p=0.056). CONCLUSION ESRα P0 promoter hypermethylation may occur in the early stages of breast carcinogenesis, while P1 promoter methylation appears in later stages with a poor prognosis. Therefore, methylation of the ESRα promoter and other tumor-related genes could serve as a potential biomarker for predicting fibroadenoma progression risk to BCa.
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Affiliation(s)
- Sylvia Dasi
- Howard University Cancer Center, Howard University, Washington, DC, U.S.A
| | | | - Bernard Kwabi-Addo
- Department of Biochemistry and Molecular Biology, Howard University College of Medicine, Howard University, Washington, DC, U.S.A
| | - Victor Apprey
- Howard University Cancer Center, Howard University, Washington, DC, U.S.A
| | - Desta Beyene
- Howard University Cancer Center, Howard University, Washington, DC, U.S.A
| | - Robert L Dewitty
- Department of Surgery, Howard University Hospital, Washington, DC, U.S.A
| | - Steven Nagel
- Department of Surgery, Howard University Hospital, Washington, DC, U.S.A
| | - Robin Williams
- Department of Surgery, Howard University Hospital, Washington, DC, U.S.A
| | - Kelly Bolden
- Department of Surgery, Howard University Hospital, Washington, DC, U.S.A
| | - Andrea Hayes-Dixon
- Department of Surgery, Howard University Hospital, Washington, DC, U.S.A
| | - Babak Shokrani
- Department of Pathology, Howard University Hospital, Washington, DC, U.S.A
| | - Delisha A Stewart
- Department of Microbiology, Howard University College of Medicine, Howard University, Washington, DC, U.S.A
| | - Olakunle O Kassim
- Department of Microbiology, Howard University College of Medicine, Howard University, Washington, DC, U.S.A
| | - Robert L Copeland
- Department of Pharmacology, Howard University College of Medicine, Howard University, Washington, DC, U.S.A
| | - Yasmine M Kanaan
- Howard University Cancer Center, Howard University, Washington, DC, U.S.A.;
- Department of Microbiology, Howard University College of Medicine, Howard University, Washington, DC, U.S.A
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de Melo Viana TC, Nakamura ET, Park A, Filardi KFXC, de Almeida Leite RM, Baltazar LFSR, Usón Junior PLS, Tustumi F. Molecular Abnormalities and Carcinogenesis in Barrett's Esophagus: Implications for Cancer Treatment and Prevention. Genes (Basel) 2025; 16:270. [PMID: 40149421 PMCID: PMC11942460 DOI: 10.3390/genes16030270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 02/16/2025] [Accepted: 02/23/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Barrett's esophagus (BE) is described by the transformation of the normal squamous epithelium into metaplastic columnar epithelium, driven by chronic gastroesophageal reflux disease (GERD). BE is a recognized premalignant condition and the main precursor to esophageal adenocarcinoma (EAC). Understanding the molecular mechanisms underlying BE carcinogenesis is crucial for improving prevention, surveillance, and treatment strategies. METHODS This narrative review examines the molecular abnormalities associated with the progression of BE to EAC. RESULTS This study highlights inflammatory, genetic, epigenetic, and chromosomal alterations, emphasizing key pathways and biomarkers. BE progression follows a multistep process involving dysplasia and genetic alterations such as TP53 and CDKN2A (p16) mutations, chromosomal instability, and dysregulation of pathways like PI3K/AKT/mTOR. Epigenetic alterations, including aberrant microRNA expression or DNA methylation, further contribute to this progression. These molecular changes are stage-specific, with some alterations occurring early in BE during the transition to high-grade dysplasia or EAC. Innovations in chemoprevention, such as combining proton pump inhibitors and aspirin, and the potential of antireflux surgery to halt disease progression are promising. Incorporating molecular biomarkers into surveillance strategies and advancing precision medicine may enable earlier detection and personalized treatments. CONCLUSIONS BE is the primary preneoplastic condition for EAC. A deeper understanding of its molecular transformation can enhance surveillance protocols, optimize the management of gastroesophageal reflux inflammation, and refine prevention and therapeutic strategies, ultimately contributing to a reduction in the global burden of EAC.
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Affiliation(s)
| | | | - Amanda Park
- Department of Evidenced-Based Medicine, Centro Universitário Lusíada, Santos 11050-071, Brazil
| | | | | | | | | | - Francisco Tustumi
- Department of Gastroenterology, Universidade de Sao Paulo, Sao Paulo 05508-220, Brazil
- Department of Health Sciences, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil
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Ram M, Fraser MR, Vieira dos Santos J, Tasakis R, Islam A, Abo-Donia JU, Parekh S, Lagana A. The Genetic and Molecular Drivers of Multiple Myeloma: Current Insights, Clinical Implications, and the Path Forward. Pharmgenomics Pers Med 2024; 17:573-609. [PMID: 39723112 PMCID: PMC11669356 DOI: 10.2147/pgpm.s350238] [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: 05/18/2024] [Accepted: 12/13/2024] [Indexed: 12/28/2024] Open
Abstract
Background Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of malignant plasma cells within the bone marrow. The disease's complexity is underpinned by a variety of genetic and molecular abnormalities that drive its progression. Methods This review was conducted through a state-of-The-art literature search, primarily utilizing PubMed to gather peer-reviewed articles. We focused on the most comprehensive and cited studies to ensure a thorough understanding of the genetic and molecular landscapes of MM. Results We detail primary and secondary alterations such as translocations, hyperdiploidy, single nucleotide variants (SNVs), copy number alterations (CNAs), gene fusions, epigenetic modifications, non-coding RNAs, germline predisposing variants, and the influence of the tumor microenvironment (TME). Our analysis highlights the heterogeneity of MM and the challenges it poses in treatment and prognosis, emphasizing the distinction between driver mutations, which actively contribute to oncogenesis, and passenger mutations, which arise due to genomic instability and do not contribute to disease progression. Conclusion & Future Perspectives We report key controversies and challenges in defining the genetic drivers of MM, and examine their implications for future therapeutic strategies. We discuss the importance of systems biology approaches in understanding the dependencies and interactions among these alterations, particularly highlighting the impact of double and triple-hit scenarios on disease outcomes. By advancing our understanding of the molecular drivers and their interactions, this review sets the stage for novel therapeutic targets and strategies, ultimately aiming to improve clinical outcomes in MM patients.
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Affiliation(s)
- Meghana Ram
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Junia Vieira dos Santos
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Rafail Tasakis
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ariana Islam
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jannah Usama Abo-Donia
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Samir Parekh
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alessandro Lagana
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Yu X, Zhang H, Zhang H, Hou C, Wang X, Gu P, Han Y, Yang Z, Zou W. The role of epigenetic methylations in thyroid Cancer. World J Surg Oncol 2024; 22:281. [PMID: 39456011 PMCID: PMC11515417 DOI: 10.1186/s12957-024-03568-2] [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: 04/26/2024] [Accepted: 10/19/2024] [Indexed: 10/28/2024] Open
Abstract
Thyroid cancer (TC) represents one of the most prevalent endocrine malignancies, with a rising incidence worldwide. Epigenetic alterations, which modify gene expression without altering the underlying DNA sequence, have garnered significant attention in recent years. Increasing evidence underscores the pivotal role of epigenetic modifications, including DNA methylation, RNA methylation, and histone methylation, in the pathogenesis of TC. This review provides a comprehensive overview of these reversible and environmentally influenced epigenetic modifications, highlighting their molecular mechanisms and functional roles in TC. Additionally, the clinical implications, challenges associated with studying these epigenetic modifications, and potential future research directions are explored.
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Affiliation(s)
- Xiaojie Yu
- Department of Thyroid Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, 256603, P.R. China
| | - Hao Zhang
- Department of Thyroid Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, 256603, P.R. China
| | - Haojie Zhang
- Department of Thyroid Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, 256603, P.R. China
| | - Changran Hou
- Department of Thyroid Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, 256603, P.R. China
| | - Xiaohong Wang
- Department of Breast Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, 256603, P.R. China
| | - Pengfei Gu
- Department of Thyroid Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, 256603, P.R. China
| | - Yong Han
- Department of Thyroid Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, 256603, P.R. China.
| | - Zhenlin Yang
- Department of Thyroid Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, 256603, P.R. China.
| | - Weiwei Zou
- Department of Thyroid Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, 256603, P.R. China.
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Seem K, Kaur S, Kumar S, Mohapatra T. Epigenome editing for targeted DNA (de)methylation: a new perspective in modulating gene expression. Crit Rev Biochem Mol Biol 2024; 59:69-98. [PMID: 38440883 DOI: 10.1080/10409238.2024.2320659] [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: 12/15/2023] [Accepted: 02/15/2024] [Indexed: 03/06/2024]
Abstract
Traditionally, it has been believed that inheritance is driven as phenotypic variations resulting from changes in DNA sequence. However, this paradigm has been challenged and redefined in the contemporary era of epigenetics. The changes in DNA methylation, histone modification, non-coding RNA biogenesis, and chromatin remodeling play crucial roles in genomic functions and regulation of gene expression. More importantly, some of these changes are inherited to the next generations as a part of epigenetic memory and play significant roles in gene expression. The sum total of all changes in DNA bases, histone proteins, and ncRNA biogenesis constitutes the epigenome. Continuous progress in deciphering epigenetic regulations and the existence of heritable epigenetic/epiallelic variations associated with trait of interest enables to deploy epigenome editing tools to modulate gene expression. DNA methylation marks can be utilized in epigenome editing for the manipulation of gene expression. Initially, genome/epigenome editing technologies relied on zinc-finger protein or transcriptional activator-like effector protein. However, the discovery of clustered regulatory interspaced short palindromic repeats CRISPR)/deadCRISPR-associated protein 9 (dCas9) enabled epigenome editing to be more specific/efficient for targeted DNA (de)methylation. One of the major concerns has been the off-target effects, wherein epigenome editing may unintentionally modify gene/regulatory element which may cause unintended change/harmful effects. Moreover, epigenome editing of germline cell raises several ethical/safety issues. This review focuses on the recent developments in epigenome editing tools/techniques, technological limitations, and future perspectives of this emerging technology in therapeutics for human diseases as well as plant improvement to achieve sustainable developmental goals.
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Affiliation(s)
- Karishma Seem
- Division of Biochemistry, ICAR-Indian Agricultural Research Institute, New Delhi, India
| | - Simardeep Kaur
- Division of Biochemistry, ICAR-Indian Agricultural Research Institute, New Delhi, India
| | - Suresh Kumar
- Division of Biochemistry, ICAR-Indian Agricultural Research Institute, New Delhi, India
| | - Trilochan Mohapatra
- Protection of Plant Varieties and Farmers' Rights Authority, New Delhi, India
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Ulschmid CM, Sun MR, Jabbarpour CR, Steward AC, Rivera-González KS, Cao J, Martin AA, Barnes M, Wicklund L, Madrid A, Papale LA, Joseph DB, Vezina CM, Alisch RS, Lipinski RJ. Disruption of DNA methylation-mediated cranial neural crest proliferation and differentiation causes orofacial clefts in mice. Proc Natl Acad Sci U S A 2024; 121:e2317668121. [PMID: 38194455 PMCID: PMC10801837 DOI: 10.1073/pnas.2317668121] [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: 10/11/2023] [Accepted: 11/14/2023] [Indexed: 01/11/2024] Open
Abstract
Orofacial clefts of the lip and palate are widely recognized to result from complex gene-environment interactions, but inadequate understanding of environmental risk factors has stymied development of prevention strategies. We interrogated the role of DNA methylation, an environmentally malleable epigenetic mechanism, in orofacial development. Expression of the key DNA methyltransferase enzyme DNMT1 was detected throughout palate morphogenesis in the epithelium and underlying cranial neural crest cell (cNCC) mesenchyme, a highly proliferative multipotent stem cell population that forms orofacial connective tissue. Genetic and pharmacologic manipulations of DNMT activity were then applied to define the tissue- and timing-dependent requirement of DNA methylation in orofacial development. cNCC-specific Dnmt1 inactivation targeting initial palate outgrowth resulted in OFCs, while later targeting during palatal shelf elevation and elongation did not. Conditional Dnmt1 deletion reduced cNCC proliferation and subsequent differentiation trajectory, resulting in attenuated outgrowth of the palatal shelves and altered development of cNCC-derived skeletal elements. Finally, we found that the cellular mechanisms of cleft pathogenesis observed in vivo can be recapitulated by pharmacologically reducing DNA methylation in multipotent cNCCs cultured in vitro. These findings demonstrate that DNA methylation is a crucial epigenetic regulator of cNCC biology, define a critical period of development in which its disruption directly causes OFCs, and provide opportunities to identify environmental influences that contribute to OFC risk.
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Affiliation(s)
- Caden M. Ulschmid
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI53706
| | - Miranda R. Sun
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI53706
| | - Christopher R. Jabbarpour
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI53706
| | - Austin C. Steward
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI53706
| | - Kenneth S. Rivera-González
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI53706
- Molecular and Environmental Toxicology Training Program, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI53706
| | - Jocelyn Cao
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI53706
| | - Alexander A. Martin
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI53706
| | - Macy Barnes
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI53706
| | - Lorena Wicklund
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI53706
| | - Andy Madrid
- Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI53706
| | - Ligia A. Papale
- Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI53706
| | - Diya B. Joseph
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI53706
| | - Chad M. Vezina
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI53706
- Molecular and Environmental Toxicology Training Program, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI53706
| | - Reid S. Alisch
- Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI53706
| | - Robert J. Lipinski
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI53706
- Molecular and Environmental Toxicology Training Program, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI53706
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Li K, Qi L, Tang G, Xu H, Li Z, Fan B, Li Z, Li Y. Epigenetic Regulation in Urothelial Carcinoma. Curr Mol Med 2024; 24:85-97. [PMID: 36545729 DOI: 10.2174/1566524023666221221094432] [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: 05/24/2022] [Revised: 11/08/2022] [Accepted: 11/10/2022] [Indexed: 12/24/2022]
Abstract
Urothelial carcinoma (UC) is a common malignancy that remains a clinical challenge: Non-muscle-invasive urothelial carcinoma (NMIUC) has a high rate of recurrence and risk of progression, while muscle-invasive urothelial carcinoma (MIUC) has a high mortality. Although some new treatments, such as immunotherapies, have shown potential effects on some patients, most cases of advanced UC remain incurable. While treatments based on epigenetic mechanisms, whether combined with traditional platinum-based chemotherapy or emerging immunotherapy, show therapeutic advantages. With the advancement of sequencing and bioinformatics, the study of epigenomics, containing DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA, is increasingly linked with the occurrence and progression of UC. Since the epigenetics of UC is a constantly developing field of medicine, this review aims to summarize the latest research on epigenetic regulation of UC, generalize the mechanism of epigenetics in UC, and reveal the potential epigenetic therapies in the clinical setting, in order to provide some new clues on the discovery of new drugs based on the epigenetics.
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Affiliation(s)
- Ke Li
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Lin Qi
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Guyu Tang
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Haozhe Xu
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Zhi Li
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Bo Fan
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Zhongbei Li
- College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Yuan Li
- Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, China
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10
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Bhunia MM, Stehn CM, Jubenville TA, Novacek EL, Larsson AT, Madala M, Suppiah S, Velez-Reyes GL, Williams KB, Sokolowski M, Williams RL, Finnerty SJ, Temiz NA, Caride A, Bhagwate AV, Nagaraj NK, Lee JH, Ordog T, Zadeh G, Largaespada DA. Multiomic analyses reveal new targets of polycomb repressor complex 2 in Schwann lineage cells and malignant peripheral nerve sheath tumors. Neurooncol Adv 2024; 6:vdae188. [PMID: 39620202 PMCID: PMC11606644 DOI: 10.1093/noajnl/vdae188] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2025] Open
Abstract
Background Malignant peripheral nerve sheath tumors (MPNSTs) can arise from atypical neurofibromas (ANF). Loss of the polycomb repressor complex 2 (PRC2) is a common event. Previous studies on PRC2-regulated genes in MPNST used genetic add-back experiments in highly aneuploid MPNST cell lines which may miss PRC2-regulated genes in NF1-mutant ANF-like precursor cells. A set of PRC2-regulated genes in human Schwann cells (SCs) has not been defined. We hypothesized that PRC2 loss has direct and indirect effects on gene expression resulting in MPNST, so we sought to identify PRC2-regulated genes in immortalized human Schwann cells (iHSCs). Methods We engineered NF1-deficient iHSCs with loss of function SUZ12 or EED mutations. RNA sequencing revealed 1327 differentially expressed genes to define PRC2-regulated genes. To investigate MPNST pathogenesis, we compared genes in iHSCs to consistent gene expression differences between ANF and MPNSTs. Chromatin immunoprecipitation sequencing was used to further define targets. Methylome and proteomic analyses were performed to further identify enriched pathways. Results We identified potential PRC2-regulated drivers of MPNST progression. Pathway analysis indicates many upregulated cancer-related pathways. We found transcriptional evidence for activated Notch and Sonic Hedgehog (SHH) signaling in PRC2-deficient iHSCs. Functional studies confirm that Notch signaling is active in MPNST cell lines, patient-derived xenografts, and transient cell models of PRC2 deficiency. A combination of MEK and γ-secretase inhibition shows synergy in MPNST cell lines. Conclusions We identified PRC2-regulated genes and potential drivers of MPNSTs. Our findings support the Notch pathway as a druggable target in MPNSTs. Our identification of PRC2-regulated genes and pathways could result in more novel therapeutic approaches.
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Affiliation(s)
- Minu M Bhunia
- Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota, USA
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Christopher M Stehn
- Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota, USA
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Tyler A Jubenville
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Ethan L Novacek
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Alex T Larsson
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Mahathi Madala
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Suganth Suppiah
- MacFeeters-Hamilton Center for Neuro-Oncology, Princess Margaret Cancer Center, Toronto, Ontario, Canada
- Division of Neurosurgery, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Germán L Velez-Reyes
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Kyle B Williams
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Mark Sokolowski
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Rory L Williams
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Samuel J Finnerty
- Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota, USA
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Nuri A Temiz
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Ariel Caride
- Epigenomics Development Laboratory, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Aditya V Bhagwate
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - Nagaswaroop K Nagaraj
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - Jeong-Heon Lee
- Epigenomics Development Laboratory, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Tamas Ordog
- Epigenomics Development Laboratory, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Gelareh Zadeh
- MacFeeters-Hamilton Center for Neuro-Oncology, Princess Margaret Cancer Center, Toronto, Ontario, Canada
- Division of Neurosurgery, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - David A Largaespada
- Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota, USA
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
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11
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Tabrizian N, Nouruzi S, Cui CJ, Kobelev M, Namekawa T, Lodhia I, Talal A, Sivak O, Ganguli D, Zoubeidi A. ASCL1 is activated downstream of the ROR2/CREB signaling pathway to support lineage plasticity in prostate cancer. Cell Rep 2023; 42:112937. [PMID: 37552603 DOI: 10.1016/j.celrep.2023.112937] [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: 02/22/2023] [Revised: 07/16/2023] [Accepted: 07/20/2023] [Indexed: 08/10/2023] Open
Abstract
Lineage plasticity is a form of therapy-induced drug resistance. In prostate cancer, androgen receptor (AR) pathway inhibitors potentially lead to the accretion of tumor relapse with loss of AR signaling and a shift from a luminal state to an alternate program. However, the molecular and signaling mechanisms orchestrating the development of lineage plasticity under the pressure of AR-targeted therapies are not fully understood. Here, a survey of receptor tyrosine kinases (RTKs) identifies ROR2 as the top upregulated RTK following AR pathway inhibition, which feeds into lineage plasticity by promoting stem-cell-like and neuronal networks. Mechanistically, ROR2 activates the ERK/CREB signaling pathway to modulate the expression of the lineage commitment transcription factor ASCL1. Collectively, our findings nominate ROR2 as a potential therapeutic target to reverse the ENZ-induced plastic phenotype and potentially re-sensitize tumors to AR pathway inhibitors.
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Affiliation(s)
- Nakisa Tabrizian
- Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
| | - Shaghayegh Nouruzi
- Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
| | - Cassandra Jingjing Cui
- Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
| | - Maxim Kobelev
- Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
| | - Takeshi Namekawa
- Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
| | - Ishana Lodhia
- Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
| | - Amina Talal
- Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
| | - Olena Sivak
- Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
| | | | - Amina Zoubeidi
- Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
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12
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Zhang Q, Liu Y, Liao J, Wu R, Zhan Y, Zhang P, Luo S. Deficiency of p53 Causes the Inadequate Expression of miR-1246 in B Cells of Systemic Lupus Erythematosus. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:1492-1498. [PMID: 36165173 PMCID: PMC9527209 DOI: 10.4049/jimmunol.2200307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 08/15/2022] [Indexed: 01/04/2023]
Abstract
Underexpression of p53 is considered the leading cause of the decreased miR-1246 expression in B cells of systemic lupus erythematosus (SLE) patients, yet the exact mechanism of action still remains unclear. To further explore the molecular mechanism of p53 upregulating miR-1246 expression, we targeted the methylation and acetylation of histone H3 in the miR-1246 promoter region of SLE B cells. We found that increased histone H3 trimethylation at Lys27 (H3K27me3) and decreased histone H3 acetylation at Lys9 and Lys14 (H3K9/K14ac) in the miR-1246 promoter region are essential for the low expression of miR-1246 in SLE B cells. p53 can promote miR-1246 transcription by recruiting Jumonji domain-containing protein 3 (JMJD3), E1A-binding protein p300 (EP300), and CREB-binding protein (CBP) to bind to the miR-1246 promoter, downregulating H3K27me3 and upregulating H3K9/K14ac. Furthermore, early B cell factor 1 (EBF1), CD40, CD38, and X box binding protein-1 (XBP-1) expression levels in SLE B cells transfected with p53 expression plasmid were significantly decreased, whereas autoantibody IgG production in autologous CD4+ T cells cocultured with overexpressed p53 SLE B cells was reduced. Collectively, our data suggest that the reduction of p53 decreases miR-1246 expression via upregulation of H3K27me3 and downregulation of H3K9/14ac, which in turn results in SLE B cell hyperactivity.
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Affiliation(s)
- Qing Zhang
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yu Liu
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jieyue Liao
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ruifang Wu
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yi Zhan
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Peng Zhang
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shuangyan Luo
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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13
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Yamagishi M. The role of epigenetics in T-cell lymphoma. Int J Hematol 2022; 116:828-836. [PMID: 36239901 DOI: 10.1007/s12185-022-03470-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 10/06/2022] [Accepted: 10/06/2022] [Indexed: 10/17/2022]
Abstract
Malignant lymphomas are a group of diseases with epigenomic abnormalities fundamental to pathogenesis and pathophysiology. They are characterized by a high frequency of abnormalities related to DNA methylation regulators (DNMT3A, TET2, IDH2, etc.) and histone modifiers (EZH2, HDAC, KMT2D/MLL2, CREBBP, EP300, etc.). These epigenomic abnormalities directly amplify malignant clones. They also originate from a hematopoietic stem cell-derived cell lineage triggered by epigenomic changes. These characteristics are linked to their high affinity for epigenomic therapies. Hematology has led disease epigenetics in the areas of basic research, clinical research, and drug discovery. However, epigenomic regulation is generally recognized as a complex system, and gaps exist between basic and clinical research. To provide an overview of the status and importance of epigenomic abnormalities in malignant lymphoma, this review first summarizes the concept and essential importance of the epigenome, then outlines the current status and future outlook of epigenomic abnormalities in malignant lymphomas.
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Affiliation(s)
- Makoto Yamagishi
- Laboratory of Tumor Cell Biology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
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14
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Decreased Jumonji Domain-Containing 3 at the Promoter Downregulates Hematopoietic Progenitor Kinase 1 Expression and Cytoactivity of T Follicular Helper Cells from Systemic Lupus Erythematosus Patients. J Immunol Res 2022; 2022:3690892. [PMID: 36213329 PMCID: PMC9534702 DOI: 10.1155/2022/3690892] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 09/15/2022] [Indexed: 11/19/2022] Open
Abstract
T follicular helper (Tfh) cells are overactivated in systemic lupus erythematosus (SLE) patients and contribute to excessive immunity. Hematopoietic progenitor kinase 1 (HPK1), as an inhibitor of T cells, is underexpressed in SLE Tfh cells and consequently induces autoimmunity. However, the reason for downregulation of HPK1 in SLE Tfh cells remains elusive. By combining chromatin immunoprecipitation with quantitative polymerase chain reaction assays, it was found that histone H3 lysine 27 trimethylation (H3K27me3) at the HPK1 promoter in SLE Tfh cells elevated greatly. We also confirmed jumonji domain-containing 3 (JMJD3) binding at the HPK1 promoter in SLE Tfh cells reduced profoundly. Knocking down JMJD3 in normal Tfh cells with siRNA alleviated enrichments of JMJD3, H3K4me3, and mixed-lineage leukemia (MLL) 1 at the HPK1 promoter and increased H3K27me3 number in the region. HPK1 expression was lowered, while Tfh cell proliferation activity, IL-21 and IFNγ secretions in the supernatants of Tfh cells, and IgG1 and IgG3 concentrations in the supernatants of Tfh-B cell cocultures all upregulated markedly. In contrast, elevating JMJD3 amount in SLE Tfh cells by JMJD3-overexpressed plasmid showed opposite effects. The abundances of H3K4me3 and MLL1 at the HPK1 promoter in SLE Tfh cells were greatly attenuated. Our results suggest that deficient JMJD3 binding at the promoter dampens HPK1 expression in SLE Tfh cells, thus making Tfh cells overactive, and ultimately results in onset of SLE.
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15
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Chen YH, Chen CH, Chien CY, Su YY, Luo SD, Li SH. JMJD3 suppresses tumor progression in oral tongue squamous cell carcinoma patients receiving surgical resection. PeerJ 2022; 10:e13759. [PMID: 35855897 PMCID: PMC9288160 DOI: 10.7717/peerj.13759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 06/29/2022] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Jumonji domain-containing-3 (JMJD3) is reported to be a histone H3 lysine 27 (H3K27) demethylase and a tumor suppressor gene. The present study designed to investigate the crucial role of JMJD3 in oral tongue squamous cell carcinoma (OTSCC) patients who received surgical resection. METHODS We enrolled a total of 156 OTSCC patients receiving surgical resection, including 73 patients (47%) with high expression of JMJD3 and 83 patients (53%) harboring low expression of JMJD3. Two OTSCC cell lines, SAS and Cal 27, were used to explore the modulation of cancer. GSK-J4, a potent inhibitor of JMJD3, was used to treat the two OTSCC cell lines. The Chi-square test was performed to examine between-group differences in categorical variables; the Kaplan-Meier method was used to investigate survival outcome in univariate analysis, and the Cox regression model was used for multivariate analysis. RESULTS The median follow-up period was 59.2 months and he five-year disease-free survival (DFS) and overall survival (OS) rates were 46.2% and 50.0%, respectively. Better five-year DFS (59% versus 35%) and five-year OS (63% versus 39%) were mentioned in patients with high expression of JMJD3 compared to those with low expression of JMJD3. High expression of JMJD3 was significantly associated with superior DFS and OS in the univariate and multivariate analyses. Following successful inhibition of JMJD3 by GSK-J4, western blotting analysis showed the decreased expression of Rb and p21. CONCLUSION Our study showed that high expression of JMJD3 is a good prognostic factor in OTSCC patients who underwent surgical resection.
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Affiliation(s)
- Yen-Hao Chen
- Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Nursing, School of Nursing, Fooyin University, Kaohsiung, Taiwan
| | - Chang-Han Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chih-Yen Chien
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Yan-Ye Su
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Sheng-Dean Luo
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Shau-Hsuan Li
- Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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16
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ASCL1 activates neuronal stem cell-like lineage programming through remodeling of the chromatin landscape in prostate cancer. Nat Commun 2022; 13:2282. [PMID: 35477723 PMCID: PMC9046280 DOI: 10.1038/s41467-022-29963-5] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 04/08/2022] [Indexed: 12/21/2022] Open
Abstract
Treatment with androgen receptor pathway inhibitors (ARPIs) in prostate cancer leads to the emergence of resistant tumors characterized by lineage plasticity and differentiation toward neuroendocrine lineage. Here, we find that ARPIs induce a rapid epigenetic alteration mediated by large-scale chromatin remodeling to support activation of stem/neuronal transcriptional programs. We identify the proneuronal transcription factor ASCL1 motif to be enriched in hyper-accessible regions. ASCL1 acts as a driver of the lineage plastic, neuronal transcriptional program to support treatment resistance and neuroendocrine phenotype. Targeting ASCL1 switches the neuroendocrine lineage back to the luminal epithelial state. This effect is modulated by disruption of the polycomb repressive complex-2 through UHRF1/AMPK axis and change the chromatin architecture in favor of luminal phenotype. Our study provides insights into the epigenetic alterations induced by ARPIs, governed by ASCL1, provides a proof of principle of targeting ASCL1 to reverse neuroendocrine phenotype, support luminal conversion and re-addiction to ARPIs. Following androgen receptor pathway inhibition prostate cancers can differentiate towards the neuroendocrine lineage. Here, the authors identify epigenetic alterations regulated by ASCL1 and suggest targeting ASCL1 to reverse the neuroendocrine phenotype.
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17
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Zhang Q, Ouyang Z, song X, Zhu W, Tang X, Liu Z, Chen X. Epigenetic modifications of tumor necrosis factor-alpha in joint cartilage tissue from osteoarthritis patients - CONSORT. Medicine (Baltimore) 2021; 100:e27868. [PMID: 34941032 PMCID: PMC8702089 DOI: 10.1097/md.0000000000027868] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Accepted: 11/03/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Osteoarthritis (OA) remains one of the most common osteopathy for centuries, which can be attributed to multiple risk factors including mechanical and biochemical ones. More and more studies verified that inflammatory cytokines play important roles in the progression of OA, such as tumor necrosis factor-alpha (TNF-α). In this study, we aimed to investigate the relationship between epigenetic manifestations of TNF-? and the pathogenesis of OA. METHODS Totally, 37 OA patients' cartilage was collected through the knee joint and 13 samples of articular cartilage as healthy control was collected through traumatic amputation. Real-time PCR, Western blot and ELISA analysis were performed to observe the expression of target genes and proteins in collected samples. RESULTS Compared with the healthy control group, TNF-? was over-expressing in cartilage which was collected from OA patients. DNA hypomethylation, histone hyperacetylation and histone methylation were observed in the TNF-? promoter in OA compared with normal patients, and we also studied series of enzymes associated with epigenetics. The results showed that by increasing DNA methylation and decreasing histone acetylation in the TNF-? promoter, and TNF-? over-expression in OA cartilage was suppressed, histone methylation has no significant correlation with OA. CONCLUSION In conclusion, the changes of epigenetic status regulate TNF-α expression in the cells, which are pivotal to the OA disease process. These results may give us a better understanding of OA and may provide new therapeutic options.
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Affiliation(s)
- Qiang Zhang
- Department of Orthopedics, the Central Hospital of Xiangtan City, Xiangtan, Hunan, P.R. China
| | - Zhengxiao Ouyang
- Department of Orthopaedic, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaoxia song
- Department of Respiratory Medicine, the Central Hospital of Xiangtan City, Xiangtan, Hunan, P.R. China
| | - Wei Zhu
- Department of Orthopedics, the Central Hospital of Changsha City, Changsha, Hunan, P.R. China
| | - Xinqiao Tang
- Department of Orthopedics, the Central Hospital of Xiangtan City, Xiangtan, Hunan, P.R. China
| | - Zhong Liu
- Department of Orthopedics, the Central Hospital of Xiangtan City, Xiangtan, Hunan, P.R. China
| | - Xiaoming Chen
- Department of Orthopedics, the Central Hospital of Xiangtan City, Xiangtan, Hunan, P.R. China
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18
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Borkiewicz L. Histone 3 Lysine 27 Trimethylation Signature in Breast Cancer. Int J Mol Sci 2021; 22:12853. [PMID: 34884658 PMCID: PMC8657745 DOI: 10.3390/ijms222312853] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/22/2021] [Accepted: 11/26/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer development and progression rely on complicated genetic and also epigenetic changes which regulate gene expression without altering the DNA sequence. Epigenetic mechanisms such as DNA methylation, histone modifications, and regulation by lncRNAs alter protein expression by either promoting gene transcription or repressing it. The presence of so-called chromatin modification marks at various gene promoters and gene bodies is associated with normal cell development but also with tumorigenesis and progression of different types of cancer, including the most frequently diagnosed breast cancer. This review is focused on the significance of one of the abundant post-translational modifications of histone 3- trimethylation of lysine 27 (H3K27me3), which was shown to participate in tumour suppressor genes' silencing. Unlike other reviews in the field, here the overview of existing evidence linking H3K27me3 status with breast cancer biology and the tumour outcome is presented especially in the context of diverse breast cancer subtypes. Moreover, the potential of agents that target H3K27me3 for the treatment of this complex disease as well as H3K27 methylation in cross-talk with other chromatin modifications and lncRNAs are discussed.
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Affiliation(s)
- Lidia Borkiewicz
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-059 Lublin, Poland
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19
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Chen X, Xia Z, Wan Y, Huang P. Identification of hub genes and candidate drugs in hepatocellular carcinoma by integrated bioinformatics analysis. Medicine (Baltimore) 2021; 100:e27117. [PMID: 34596112 PMCID: PMC8483840 DOI: 10.1097/md.0000000000027117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 08/14/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the third cancer-related cause of death in the world. Until now, the involved mechanisms during the development of HCC are largely unknown. This study aims to explore the driven genes and potential drugs in HCC. METHODS Three mRNA expression datasets were used to analyze the differentially expressed genes (DEGs) in HCC. The bioinformatics approaches include identification of DEGs and hub genes, Gene Ontology terms analysis and Kyoto encyclopedia of genes and genomes enrichment analysis, construction of protein-protein interaction network. The expression levels of hub genes were validated based on The Cancer Genome Atlas, Gene Expression Profiling Interactive Analysis, and the Human Protein Atlas. Moreover, overall survival and disease-free survival analysis of HCC patients were further conducted by Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis. DGIdb database was performed to search the candidate drugs for HCC. RESULTS A total of 197 DEGs were identified. The protein-protein interaction network was constructed using Search Tool for the Retrieval of Interacting Genes software, 10 genes were selected by Cytoscape plugin cytoHubba and served as hub genes. These 10 genes were all closely related to the survival of HCC patients. DGIdb database predicted 29 small molecules as the possible drugs for treating HCC. CONCLUSION Our study provides some new insights into HCC pathogenesis and treatments. The candidate drugs may improve the efficiency of HCC therapy in the future.
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Affiliation(s)
- Xiaolong Chen
- National Key Clinical Department, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhixiong Xia
- Department of Pathology, The Center Hospital of Wuhan, Hubei, China
| | - Yafeng Wan
- Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Ping Huang
- National Key Clinical Department, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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20
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Oh S, Cho Y, Chang M, Park S, Kwon H. Metformin Decreases 2-HG Production through the MYC-PHGDH Pathway in Suppressing Breast Cancer Cell Proliferation. Metabolites 2021; 11:metabo11080480. [PMID: 34436421 PMCID: PMC8402004 DOI: 10.3390/metabo11080480] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 11/29/2022] Open
Abstract
The biguanide drug metformin has been widely used for the treatment of type 2 diabetes, and there is evidence supporting the anticancer effect of metformin despite some controversy. Here, we report the growth inhibitory activity of metformin in the breast cancer (MCF-7) cells, both in vitro and in vivo, and the associated metabolic changes. In particular, a decrease in a well-known oncometabolite 2-hydroxyglutarate (2-HG) was discovered by a metabolomics approach. The decrease in 2-HG by metformin was accompanied by the reduction in histone methylation, consistent with the known tumorigenic mechanism of 2-HG. The relevance of 2-HG inhibition in breast cancer was also supported by a higher level of 2-HG in human breast cancer tissues. Genetic knockdown of PHGDH identified the PHGDH pathway as the producer of 2-HG in the MCF-7 cells that do not carry isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) mutations, the conventional producer of 2-HG. We also showed that metformin’s inhibitory effect on the PHGDH-2HG axis may occur through the regulation of the AMPK-MYC pathway. Overall, our results provide an explanation for the coherent pathway from complex I inhibition to epigenetic changes for metformin’s anticancer effect.
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Affiliation(s)
- Sehyun Oh
- Natural Product Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea;
| | - Youngup Cho
- Department of Surgery, College of Medicine, Inha University, Inhang-Ro 27, Chung-gu, Incheon 22332, Korea;
| | - Minsun Chang
- Department of Biological Sciences, College of Science, Sookmyung Women’s University, 100, Cheongpa-ro 47-gil, Yongsan-gu, Seoul 140-742, Korea
- Correspondence: (M.C.); (S.P.); (H.K.)
| | - Sunghyouk Park
- Natural Product Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea;
- Correspondence: (M.C.); (S.P.); (H.K.)
| | - Hyuknam Kwon
- Natural Product Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea;
- Department of Biological and Environmental Sciences, University of Helsinki, 00160 Helsinki, Finland
- Correspondence: (M.C.); (S.P.); (H.K.)
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21
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Da Silva MLR, De Albuquerque BHDR, Allyrio TADMF, De Almeida VD, Cobucci RNDO, Bezerra FL, Andrade VS, Lanza DCF, De Azevedo JCV, De Araújo JMG, Fernandes JV. The role of HPV-induced epigenetic changes in cervical carcinogenesis (Review). Biomed Rep 2021; 15:60. [PMID: 34094536 PMCID: PMC8165754 DOI: 10.3892/br.2021.1436] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 03/10/2021] [Indexed: 12/12/2022] Open
Abstract
Cervical cancer is associated with infection by certain types of human papillomaviruses (HPVs), and this affects women worldwide. Despite the improvements in prevention and cure of HPV-induced cervical cancer, it remains the second most common type of cancer in women in the least developed regions of the world. Epigenetic modifications are stable long-term changes that occur in the DNA, and are part of a natural evolutionary process of necessary adaptations to the environment. They do not result in changes in the DNA sequence, but do affect gene expression and genomic stability. Epigenetic changes are important in several biological processes. The effects of the environment on gene expression can contribute to the development of numerous diseases. Epigenetic modifications may serve a critical role in cancer cells, by silencing tumor suppressor genes, activating oncogenes, and exacerbating defects in DNA repair mechanisms. Although cervical cancer is directly related to a persistent high-risk HPV infection, several epigenetic changes have been identified in both the viral DNA and the genome of the infected cells: DNA methylation, histone modification and gene silencing by non-coding RNAs, which initiate and sustain epigenetic changes. In the present review, recent advances in the role of epigenetic changes in cervical cancer are summarized.
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Affiliation(s)
- Martha Laysla Ramos Da Silva
- Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil.,Post-Graduate Program in Parasite Biology, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | | | | | - Valéria Duarte De Almeida
- Department of Biomedical Sciences, State University of Rio Grande do Norte, Mossoro 59607-360, Brazil
| | | | - Fabiana Lima Bezerra
- Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - Vania Sousa Andrade
- Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil.,Post-Graduate Program in Parasite Biology, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - Daniel Carlos Ferreira Lanza
- Laboratory of Applied Molecular Biology, Department of Biochemistry, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | | | - Josélio Maria Galvão De Araújo
- Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil.,Post-Graduate Program in Parasite Biology, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - José Veríssimo Fernandes
- Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil.,Post-Graduate Program in Parasite Biology, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
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22
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Venosa A, Smith LC, Gow AJ, Zarbl H, Laskin JD, Laskin DL. Macrophage activation in the lung during the progression of nitrogen mustard induced injury is associated with histone modifications and altered miRNA expression. Toxicol Appl Pharmacol 2021; 423:115569. [PMID: 33971176 DOI: 10.1016/j.taap.2021.115569] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 12/11/2022]
Abstract
Activated macrophages have been implicated in lung injury and fibrosis induced by the cytotoxic alkylating agent, nitrogen mustard (NM). Herein, we determined if macrophage activation is associated with histone modifications and altered miRNA expression. Treatment of rats with NM (0.125 mg/kg, i.t.) resulted in increases in phosphorylation of H2A.X in lung macrophages at 1 d and 3 d post-exposure. This DNA damage response was accompanied by methylation of histone (H) 3 lysine (K) 4 and acetylation of H3K9, marks of transcriptional activation, and methylation of H3K36 and H3K9, marks associated with transcriptional repression. Increases in histone acetyl transferase and histone deacetylase were also observed in macrophages 1 d and 28 d post-NM exposure. PCR array analysis of miRNAs (miR)s involved in inflammation and fibrosis revealed unique and overlapping expression profiles in macrophages isolated 1, 3, 7, and 28 d post-NM. An IPA Core Analysis of predicted mRNA targets of differentially expressed miRNAs identified significant enrichment of Diseases and Functions related to cell cycle arrest, apoptosis, cell movement, cell adhesion, lipid metabolism, and inflammation 1 d and 28 d post NM. miRNA-mRNA interaction network analysis revealed highly connected miRNAs representing key upstream regulators of mRNAs involved in significantly enriched pathways including miR-34c-5p and miR-27a-3p at 1 d post NM and miR-125b-5p, miR-16-5p, miR-30c-5p, miR-19b-3p and miR-148b-3p at 28 d post NM. Collectively, these data show that NM promotes histone remodeling and alterations in miRNA expression linked to lung macrophage responses during inflammatory injury and fibrosis.
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Affiliation(s)
- Alessandro Venosa
- Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA
| | - L Cody Smith
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA
| | - Andrew J Gow
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA; Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA
| | - Helmut Zarbl
- Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA; Department of Environmental and Occupational Health and Justice, Rutgers University School of Public Health, Piscataway, NJ 08854, USA
| | - Jeffrey D Laskin
- Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA; Department of Environmental and Occupational Health and Justice, Rutgers University School of Public Health, Piscataway, NJ 08854, USA
| | - Debra L Laskin
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA; Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA.
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23
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Li Y, Chen X, Lu C. The interplay between DNA and histone methylation: molecular mechanisms and disease implications. EMBO Rep 2021; 22:e51803. [PMID: 33844406 PMCID: PMC8097341 DOI: 10.15252/embr.202051803] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 02/16/2021] [Accepted: 03/15/2021] [Indexed: 12/21/2022] Open
Abstract
Methylation of cytosine in CpG dinucleotides and histone lysine and arginine residues is a chromatin modification that critically contributes to the regulation of genome integrity, replication, and accessibility. A strong correlation exists between the genome-wide distribution of DNA and histone methylation, suggesting an intimate relationship between these epigenetic marks. Indeed, accumulating literature reveals complex mechanisms underlying the molecular crosstalk between DNA and histone methylation. These in vitro and in vivo discoveries are further supported by the finding that genes encoding DNA- and histone-modifying enzymes are often mutated in overlapping human diseases. Here, we summarize recent advances in understanding how DNA and histone methylation cooperate to maintain the cellular epigenomic landscape. We will also discuss the potential implication of these insights for understanding the etiology of, and developing biomarkers and therapies for, human congenital disorders and cancers that are driven by chromatin abnormalities.
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Affiliation(s)
- Yinglu Li
- Department of Genetics and Development and Herbert Irving Comprehensive Cancer CenterColumbia University Irving Medical CenterNew YorkNYUSA
| | - Xiao Chen
- Department of Genetics and Development and Herbert Irving Comprehensive Cancer CenterColumbia University Irving Medical CenterNew YorkNYUSA
| | - Chao Lu
- Department of Genetics and Development and Herbert Irving Comprehensive Cancer CenterColumbia University Irving Medical CenterNew YorkNYUSA
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24
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Sar P, Dalai S. CRISPR/Cas9 in epigenetics studies of health and disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2021; 181:309-343. [PMID: 34127198 DOI: 10.1016/bs.pmbts.2021.01.022] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Epigenetics is the heritable phenotypic changes without altering the genotype. Epigenetic processes are such as histone methylation, acetylation, ubiquitination, sumoylation, phosphorylation, ADP ribosylation, DNA methylation and non-coding RNAs interactions associated with structural changes in chromatin. The change of structure is either open chromatin for "active" state or closed chromatin for "inactive" state, that regulates important biological phenomenon like chromatin condensation, gene expression, DNA repair, cellular development, differentiation and homeostasis, etc. However, dysregulation of epigenetic patterns causes diseases like cancer, diabetes, neurological disorder, infectious diseases, autoimmunity etc. Besides, the most important clinical uses of Epigenetics studies are i. identification of disease biomarkers and ii. development of their therapeutics. Epigenetic therapies include epi-drugs, combinatorial therapy, nanocarriers, plant-derived products that are being used for changing the epigenetic pattern to reverse gene expression. However, the developed epi- drugs cause off-target gene and transposable elements activation; promote mutagenesis and carcinogenesis in normal cells, are the major hurdles regarding their clinical use. Therefore, advanced epigenetic therapeutics are required to develop target-specific epigenetic modifications to reverse gene expression pattern. CRISPR-Cas9 (Clustered Regularly Interspaced Palindrome Repeats-associated protein 9) system-mediated gene activation mechanism paves new methods of target-specific epigenetic therapeutics to cure diseases. In this chapter, we discuss how CRISPR/Cas9 and dCas9 have recently been engineered for epigenome editing. Different strategies have been discussed used for epigenome editing based on their efficacy and complexity. Last but not least we have discussed the limitations, different uses of CRISPR/Cas9 and dCas9 in the area of genetic engineering.
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Affiliation(s)
- Pranati Sar
- Institute of Science, NIRMA University, Ahmedabad, India.
| | - Sarat Dalai
- Institute of Science, NIRMA University, Ahmedabad, India.
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25
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Epigenetic regulation of TGF-β-induced EMT by JMJD3/KDM6B histone H3K27 demethylase. Oncogenesis 2021; 10:17. [PMID: 33637682 PMCID: PMC7910473 DOI: 10.1038/s41389-021-00307-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 01/26/2021] [Accepted: 02/04/2021] [Indexed: 11/22/2022] Open
Abstract
Transforming growth factor-β (TGF-β) signaling pathways are well-recognized for their role in proliferation and epithelial–mesenchymal transition (EMT) of cancer cells, but much less is understood about their contribution to interactions with other signaling events. Recent studies have indicated that crosstalk between TGF-β and Ras signaling makes a contribution to TGF-β-mediated EMT. Here, we demonstrate that Jumonji domain containing-3 (JMJD3 also called KDM6B) promotes TGF-β-mediated Smad activation and EMT in Ras-activated lung cancer cells. JMJD3 in lung cancer patients was significantly increased and JMJD3 expression in lung tumor tissues was correlated with expression of K-Ras or H-Ras in particular, and its expression was regulated by Ras activity in lung cancer cells. JMJD3 promotes TGF-β-induced Smad activation and EMT in Ras-activated lung cancer cells through the induction of syntenin, a protein that regulates TGF-β receptor activation upon ligand binding. Tissue array and ChIP analysis revealed that JMJD3 epigenetically induces syntenin expression by directly regulating H3K27 methylation levels. Mechanical exploration identified a physical and functional association of JMJD3 with syntenin presiding over the TGF-β in Ras-activated lung cancer cells. Taken together, these findings provide new insight into the mechanisms by which JMJD3 promotes syntenin expression resulting in oncogenic Ras cooperation with TGF-β to promote EMT.
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26
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Tellez CS, Picchi MA, Juri D, Do K, Desai DH, Amin SG, Hutt JA, Filipczak PT, Belinsky SA. Chromatin remodeling by the histone methyltransferase EZH2 drives lung pre-malignancy and is a target for cancer prevention. Clin Epigenetics 2021; 13:44. [PMID: 33632299 PMCID: PMC7908796 DOI: 10.1186/s13148-021-01034-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 02/18/2021] [Indexed: 12/12/2022] Open
Abstract
Background Trimethylation of lysine 27 and dimethylation of lysine 9 of histone-H3 catalyzed by the histone methyltransferases EZH2 and G9a impede gene transcription in cancer. Our human bronchial epithelial (HBEC) pre-malignancy model studied the role of these histone modifications in transformation. Tobacco carcinogen transformed HBEC lines were characterized for cytosine DNA methylation, transcriptome reprogramming, and the effect of inhibiting EZH2 and G9a on the transformed phenotype. The effects of targeting EZH2 and G9a on lung cancer prevention was assessed in the A/J mouse lung tumor model. Results Carcinogen exposure induced transformation and DNA methylation of 12–96 genes in the four HBEC transformed (T) lines that was perpetuated in malignant tumors. In contrast, 506 unmethylated genes showed reduced expression in one or more HBECTs with many becoming methylated in tumors. ChIP-on-chip for HBEC2T identified 327 and 143 genes enriched for H3K27me3 and H3K9me2. Treatment of HBEC2T and HBEC13T with DZNep, a lysine methyltransferase inhibitor depleted EZH2, reversed transformation, and induced transcriptional reprogramming. The EZH2 small molecule inhibitor EPZ6438 also affected transformation and expression in HBEC2T, while a G9a inhibitor, UNC0642 was ineffective. Genetic knock down of EZH2 dramatically reduced carcinogen-induced transformation of HBEC2. Only DZNep treatment prevented progression of hyperplasia to adenomas in the NNK mouse lung tumor model through reducing EZH2 and affecting the expression of genes regulating cell growth and invasion. Conclusion These studies demonstrate a critical role for EZH2 catalyzed histone modifications for premalignancy and its potential as a target for chemoprevention of lung carcinogenesis.
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Affiliation(s)
- Carmen S Tellez
- Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USA.
| | - Maria A Picchi
- Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USA
| | - Daniel Juri
- Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USA
| | - Kieu Do
- Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USA
| | - Dhimant H Desai
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA
| | - Shantu G Amin
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA
| | - Julie A Hutt
- Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USA
| | - Piotr T Filipczak
- Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USA
| | - Steven A Belinsky
- Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USA.
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27
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Epigenetic reprogramming during prostate cancer progression: A perspective from development. Semin Cancer Biol 2021; 83:136-151. [PMID: 33545340 DOI: 10.1016/j.semcancer.2021.01.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/27/2021] [Accepted: 01/27/2021] [Indexed: 12/15/2022]
Abstract
Conrad Waddington's theory of epigenetic landscape epitomize the process of cell fate and cellular decision-making during development. Wherein the epigenetic code maintains patterns of gene expression in pluripotent and differentiated cellular states during embryonic development and differentiation. Over the years disruption or reprogramming of the epigenetic landscape has been extensively studied in the course of cancer progression. Cellular dedifferentiation being a key hallmark of cancer allow us to take cues from the biological processes involved during development. Here, we discuss the role of epigenetic landscape and its modifiers in cell-fate determination, differentiation and prostate cancer progression. Lately, the emergence of RNA-modifications has also furthered our understanding of epigenetics in cancer. The overview of the epigenetic code regulating androgen signalling, and progression to aggressive neuroendocrine stage of PCa reinforces its gene regulatory functions during the development of prostate gland as well as cancer progression. Additionally, we also highlight the clinical implications of cancer cell epigenome, and discuss the recent advancements in the therapeutic strategies targeting the advanced stage disease.
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28
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Hu X, Estecio MR, Chen R, Reuben A, Wang L, Fujimoto J, Carrot-Zhang J, McGranahan N, Ying L, Fukuoka J, Chow CW, Pham HHN, Godoy MCB, Carter BW, Behrens C, Zhang J, Antonoff MB, Sepesi B, Lu Y, Pass HI, Kadara H, Scheet P, Vaporciyan AA, Heymach JV, Wistuba II, Lee JJ, Futreal PA, Su D, Issa JPJ, Zhang J. Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas. Nat Commun 2021; 12:687. [PMID: 33514726 PMCID: PMC7846738 DOI: 10.1038/s41467-021-20907-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 12/17/2020] [Indexed: 12/17/2022] Open
Abstract
The evolution of DNA methylome and methylation intra-tumor heterogeneity (ITH) during early carcinogenesis of lung adenocarcinoma has not been systematically studied. We perform reduced representation bisulfite sequencing of invasive lung adenocarcinoma and its precursors, atypical adenomatous hyperplasia, adenocarcinoma in situ and minimally invasive adenocarcinoma. We observe gradual increase of methylation aberrations and significantly higher level of methylation ITH in later-stage lesions. The phylogenetic patterns inferred from methylation aberrations resemble those based on somatic mutations suggesting parallel methylation and genetic evolution. De-convolution reveal higher ratio of T regulatory cells (Tregs) versus CD8 + T cells in later-stage diseases, implying progressive immunosuppression with neoplastic progression. Furthermore, increased global hypomethylation is associated with higher mutation burden, copy number variation burden and AI burden as well as higher Treg/CD8 ratio, highlighting the potential impact of methylation on chromosomal instability, mutagenesis and tumor immune microenvironment during early carcinogenesis of lung adenocarcinomas.
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Affiliation(s)
- Xin Hu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Marcos R Estecio
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Center of Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Runzhe Chen
- Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Alexandre Reuben
- Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Linghua Wang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Junya Fujimoto
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jian Carrot-Zhang
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Nicholas McGranahan
- Cancer Research United Kingdom-University College London Lung Cancer Centre of Excellence, London, SW73RP, UK
| | - Lisha Ying
- Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, 310022, Hangzhou, China
- Zhejiang Cancer Research Institute, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), 310022, Hangzhou, China
| | - Junya Fukuoka
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 8528523, Japan
| | - Chi-Wan Chow
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Hoa H N Pham
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 8528523, Japan
| | - Myrna C B Godoy
- Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Brett W Carter
- Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Carmen Behrens
- Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jianhua Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Mara B Antonoff
- Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Boris Sepesi
- Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yue Lu
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Center of Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Harvey I Pass
- Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, NY, 10016, USA
| | - Humam Kadara
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Paul Scheet
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Ara A Vaporciyan
- Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - John V Heymach
- Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Ignacio I Wistuba
- Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - J Jack Lee
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - P Andrew Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Dan Su
- Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), 310022, Hangzhou, China.
| | | | - Jianjun Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
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29
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van Dijk AD, Hoff FW, Qiu YH, Chandra J, Jabbour E, de Bont ESJM, Horton TM, Kornblau SM. Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia. Clin Epigenetics 2021; 13:21. [PMID: 33509276 PMCID: PMC7841917 DOI: 10.1186/s13148-021-01011-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 01/11/2021] [Indexed: 12/23/2022] Open
Abstract
Background Acute leukemia is an epigenetically heterogeneous disease. The intensity of treatment is currently guided by cytogenetic and molecular genetic risk classifications; however these incompletely predict outcomes, requiring additional information for more accurate outcome predictions. We aimed to identify potential prognostic implications of epigenetic modification of histone proteins, with a focus on H3K4 and H3K27 methylation marks in relation to mutations in chromatin, splicing and transcriptional regulators in adult-onset acute lymphoblastic and myeloid leukemia. Results Histone 3 lysine 4 di- and trimethylation (H3K4me2, H3K4me3) and lysine 27 trimethylation (H3K27me3) mark expression was evaluated in 241 acute myeloid leukemia (AML), 114 B-cell acute lymphoblastic leukemia (B-ALL) and 14T-cell ALL (T-ALL) patient samples at time of diagnosis using reverse phase protein array. Expression levels of the marks were significantly lower in AML than in B and T-ALL in both bone marrow and peripheral blood, as well as compared to normal CD34+ cells. In AML, greater loss of H3K27me3 was associated with increased proliferative potential and shorter overall survival in the whole patient population, as well as in subsets with DNA methylation mutations. To study the prognostic impact of H3K27me3 in the context of cytogenetic aberrations and mutations, multivariate analysis was performed and identified lower H3K27me3 level as an independent unfavorable prognostic factor in all, as well as in TP53 mutated patients. AML with decreased H3K27me3 demonstrated an upregulated anti-apoptotic phenotype. In ALL, the relative quantity of histone methylation expression correlated with response to tyrosine kinase inhibitor in patients who carried the Philadelphia cytogenetic aberration and prior smoking behavior. Conclusion This study shows that proteomic profiling of epigenetic modifications has clinical implications in acute leukemia and supports the idea that epigenetic patterns contribute to a more accurate picture of the leukemic state that complements cytogenetic and molecular genetic subgrouping. A combination of these variables may offer more accurate outcome prediction and we suggest that histone methylation mark measurement at time of diagnosis might be a suitable method to improve patient outcome prediction and subsequent treatment intensity stratification in selected subgroups.
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Affiliation(s)
- A D van Dijk
- Department of Pediatric Oncology/Hematology, University Medical Center Groningen, Groningen, The Netherlands.
| | - F W Hoff
- Department of Pediatric Oncology/Hematology, University Medical Center Groningen, Groningen, The Netherlands
| | - Y H Qiu
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - J Chandra
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - E Jabbour
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - E S J M de Bont
- Department of Pediatric Oncology/Hematology, University Medical Center Groningen, Groningen, The Netherlands
| | - T M Horton
- Department of Pediatrics, Division of Hematology/Oncology, Baylor College of Medicine, Texas Children's Cancer Center, Houston, TX, USA
| | - S M Kornblau
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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30
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Chen B, Dong C, Wang F, Wu J. Knockdown of NIR Suppresses Breast Cancer Cell Proliferation via Promoting FOXO3. Onco Targets Ther 2021; 14:637-651. [PMID: 33519211 PMCID: PMC7837597 DOI: 10.2147/ott.s287464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 12/24/2020] [Indexed: 12/09/2022] Open
Abstract
Background Novel inhibitor of histone acetyltransferase repressor (NIR), a corepressor with a novel inhibitor of histone acetyltransferase (INHAT) activity, has been reported to be a negative modulator of p53 and a regulator of the cell cycle in cancer cells. However, the role of NIR in the progression of breast cancer remains elusive. Materials and Methods Oncomine database was used to analyze the mRNA levels and prognosis value of NIR in breast cancer. We performed loss-of-function and gain-of-function studies using lentivirus expressing shRNA targeting NIR, enhancer of zeste homolog 2 (EZH2) and forkhead box O3 (FOXO3) or lentivirus expressing NIR or FOXO3, respectively. Cell proliferation and colony formation assays were performed. Co-immunoprecipitation (Co-IP) and immunoprecipitation (IP) were performed to identify the interaction between NIR and polycomb repressive complex 2 (PRC2) subunits. ChIP assay was used to identify the enrichment of NIR, EZH2, H3K27ac and H3K27me3 at the FOXO3 promoter region and the regulation of H3K27 modification at the FOXO3 promoter by NIR. Results High levels of NIR expression were correlated with poor prognosis in breast cancer patients. Knockdown of NIR suppressed the proliferation of breast cancer cells. Mechanically, NIR was recruited by EZH2 to the promoter vicinity of FOXO3 via direct protein–protein interaction. Silencing NIR increased H3K27ac and decreased H3K27me3 levels at the FOXO3 promoter, resulting in enhancing FOXO3 expression. In accordance with this, growth inhibition of breast cancer cells caused by silencing of NIR could be reversed by FOXO3 knockdown. Conclusion NIR knockdown inhibited proliferation by switching the H3K27me3 and H3K27ac marks at the FOXO3 promoter to promote FOXO3 transcription, and this effect depends on the physical interaction between NIR and PRC2 in breast cancer cells. Our results suggest that NIR might be a potential target for breast cancer treatment.
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Affiliation(s)
- Bolin Chen
- Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China
| | - Chengcheng Dong
- School of Biotechnology, Guilin Medical University, Guilin 541199, People's Republic of China
| | - Fang Wang
- School of Biotechnology, Guilin Medical University, Guilin 541199, People's Republic of China
| | - Jiacai Wu
- School of Biotechnology, Guilin Medical University, Guilin 541199, People's Republic of China.,School of Pharmacy, Guilin Medical University, Guilin 541199, People's Republic of China
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31
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To KKW, Cho WCS. Flavonoids Overcome Drug Resistance to Cancer Chemotherapy by Epigenetically Modulating Multiple Mechanisms. Curr Cancer Drug Targets 2021; 21:289-305. [PMID: 33535954 DOI: 10.2174/1568009621666210203111220] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/25/2020] [Accepted: 12/03/2020] [Indexed: 11/22/2022]
Abstract
Drug resistance is the major reason accounting for the treatment failure in cancer chemotherapy. Dysregulation of the epigenetic machineries is known to induce chemoresistance. It was reported that numerous genes encoding the key mediators in cancer proliferation, apoptosis, DNA repair, and drug efflux are dysregulated in resistant cancer cells by aberrant DNA methylation. The imbalance of various enzymes catalyzing histone post-translational modifications is also known to alter chromatin configuration and regulate multiple drug resistance genes. Alteration in miRNA signature in cancer cells also gives rise to chemoresistance. Flavonoids are a large group of naturally occurring polyphenolic compounds ubiquitously found in plants, fruits, vegetables and traditional herbs. There has been increasing research interest in the health-promoting effects of flavonoids. Flavonoids were shown to directly kill or re-sensitize resistant cancer cells to conventional anticancer drugs by epigenetic mechanisms. In this review, we summarize the current findings of the circumvention of drug resistance by flavonoids through correcting the aberrant epigenetic regulation of multiple resistance mechanisms. More investigations including the evaluation of synergistic anticancer activity, dosing sequence effect, toxicity in normal cells, and animal studies, are warranted to establish the full potential of the combination of flavonoids with conventional chemotherapeutic drugs in the treatment of cancer with drug resistance.
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Affiliation(s)
- Kenneth K W To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - William C S Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China
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32
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Shao X, Zhao T, Xi L, Zhang Y, He J, Zeng J, Deng L. LINC00565 promotes the progression of colorectal cancer by upregulating EZH2. Oncol Lett 2020; 21:53. [PMID: 33281964 PMCID: PMC7709565 DOI: 10.3892/ol.2020.12314] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 10/19/2020] [Indexed: 12/20/2022] Open
Abstract
The present study aimed to illustrate the role of LINC00565 in aggravating colorectal cancer (CRC) by targeting enhancer of zeste homolog 2 (EZH2). The relative levels of LINC00565 and EZH2 in CRC tissues, based on their Tumor-Node-Metastasis stage and tumor size, were detected by reverse transcription-quantitative polymerase chain reaction. The diagnostic value of LINC00565 in CRC was assessed by depicting receiver operating characteristic curves. Pearson's correlation test was applied to analyze the expression correlation between LINC00565 and EZH2 in CRC tissues. The transfection efficacy of three LINC00565 small interfering RNAs was examined in CRC HCT116 and SW480 cell lines. After knockdown of LINC00565, the proliferative and migratory abilities of CRC cells were detected by Cell Counting Kit-8 and Transwell assays, respectively. The subcellular distribution of LINC00565 was analyzed, and the interaction between LINC00565 and EZH2 was determined by RNA immunoprecipitation. Finally, co-regulation of LINC00565 and EZH2 on CRC cell functions was explored by performing rescue experiments. Results showed that LINC00565 was upregulated in CRC tissues, especially in patients with stage III+IV and in those with large tumor sizes, suggesting its diagnostic value in CRC. EZH2 was also upregulated in CRC tissues, showing a positive correlation with LINC00565. LINC00565 was mainly expressed in the cytoplasm and was found to bind with EZH2. Validation was performed by overexpressing EZH2, which abolished the role of silenced LINC00565 in regulating proliferative and migratory abilities in CRC. Therefore, the upregulation of LINC00565 in CRC tissues was found to stimulate the aggravation of CRC by upregulating EZH2.
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Affiliation(s)
- Xiaxia Shao
- Department of Oncology, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, Jiangsu 214400, P.R. China
| | - Tao Zhao
- Department of Oncology, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, Jiangsu 214400, P.R. China
| | - Lei Xi
- Department of Oncology, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, Jiangsu 214400, P.R. China
| | - Yuhong Zhang
- Department of Oncology, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, Jiangsu 214400, P.R. China
| | - Jia He
- Department of Oncology, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, Jiangsu 214400, P.R. China
| | - Jie Zeng
- Department of Oncology, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, Jiangsu 214400, P.R. China
| | - Lichun Deng
- Department of Oncology, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, Jiangsu 214400, P.R. China
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33
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Zhang N, Zhao C, Zhang X, Cui X, Zhao Y, Yang J, Gao X. Growth arrest-specific 2 protein family: Structure and function. Cell Prolif 2020; 54:e12934. [PMID: 33103301 PMCID: PMC7791176 DOI: 10.1111/cpr.12934] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/29/2020] [Accepted: 10/03/2020] [Indexed: 12/15/2022] Open
Abstract
Members of the growth arrest–specific 2 (GAS2) protein family consist of a putative actin‐binding (CH) domain and a microtubule‐binding (GAR) domain and are considered miniversions of spectraplakins. There are four members in the GAS2 family, viz. GAS2, GAS2L1, GAS2L2 and GAS2L3. Although GAS2 is defined as a family of growth arrest–specific proteins, the significant differences in the expression patterns, interaction characteristics and biological issues or diseases among the different GAS2 family members have not been systemically reviewed to date. Therefore, we summarized the available evidence on the structures and functions of GAS2 family members. This review facilitates a comprehensive molecular understanding of the involvement of the GAS2 family members in an array of biological processes, including cytoskeleton reorganization, cell cycle, apoptosis and cancer development.
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Affiliation(s)
- Nan Zhang
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China
| | - Chunyan Zhao
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China
| | - Xinxin Zhang
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China
| | - Xiaoteng Cui
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China.,Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Department of Neurosurgery, Tianjin Medical University General Hospital and Key Laboratory of Neurotrauma, Variation, and Regeneration, Ministry of Education and Tianjin Municipal Government, Tianjin, China
| | - Yan Zhao
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China
| | - Jie Yang
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China
| | - Xingjie Gao
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China
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34
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Ramahi A, Altorok N, Kahaleh B. Epigenetics and systemic sclerosis: An answer to disease onset and evolution? Eur J Rheumatol 2020; 7:S147-S156. [PMID: 32697935 PMCID: PMC7647676 DOI: 10.5152/eurjrheum.2020.19112] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 03/06/2020] [Indexed: 12/22/2022] Open
Abstract
There is growing evidence that implicates epigenetic modification in the pathogenesis of systemic sclerosis (SSc). The complexity of epigenetic regulation and its dynamic nature complicate the investigation of its role in the disease. We will review the current literature for factors that link epigenetics to SSc by discussing DNA methylation, histone acetylation and methylation, and non-coding RNAs (ncRNAs), particularly microRNA changes in endothelial cells, fibroblasts (FBs), and lymphocytes. These three cell types are significantly involved in the early stages and throughout the course of the disease and are particularly vulnerable to epigenetic regulation. The pathogenesis of SSc is likely related to modifications of the epigenome by environmental signals in individuals with a specific genetic makeup. The epigenome is an attractive therapeutic target; however, successful epigenetics-based treatments require a better understanding of the molecular mechanisms controlling the epigenome and its alteration in the disease.
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Affiliation(s)
- Ahmad Ramahi
- Division of Rheumatology and Immunology, Department of Internal Medicine, University of Toledo Medical Center, Toledo, OH, USA
| | - Nezam Altorok
- Division of Rheumatology and Immunology, Department of Internal Medicine, University of Toledo Medical Center, Toledo, OH, USA
| | - Bashar Kahaleh
- Division of Rheumatology and Immunology, Department of Internal Medicine, University of Toledo Medical Center, Toledo, OH, USA
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35
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Yuan H, Han Y, Wang X, Li N, Liu Q, Yin Y, Wang H, Pan L, Li L, Song K, Qiu T, Pan Q, Chen Q, Zhang G, Zang Y, Tan M, Zhang J, Li Q, Wang X, Jiang J, Qin J. SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways. Cancer Cell 2020; 38:350-365.e7. [PMID: 32619406 DOI: 10.1016/j.ccell.2020.05.022] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 04/01/2020] [Accepted: 05/28/2020] [Indexed: 12/19/2022]
Abstract
The level of SETD2-mediated H3K36me3 is inversely correlated with that of EZH2-catalyzed H3K27me3. Nevertheless, it remains unclear whether these two enzymatic activities are molecularly intertwined. Here, we report that SETD2 delays prostate cancer (PCa) metastasis via its substrate EZH2. We show that SETD2 methylates EZH2 which promotes EZH2 degradation. SETD2 deficiency induces a Polycomb-repressive chromatin state that enables cells to acquire metastatic traits. Conversely, mice harboring nonmethylated EZH2 mutant or SETD2 mutant defective in binding to EZH2 develop metastatic PCa. Furthermore, we identify that metformin-stimulated AMPK signaling converges at FOXO3 to stimulate SETD2 expression. Together, our results demonstrate that the SETD2-EZH2 axis integrates metabolic and epigenetic signaling to restrict PCa metastasis.
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Affiliation(s)
- Huairui Yuan
- CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Ying Han
- CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Xuege Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Ni Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Qiuli Liu
- Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Yuye Yin
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, NHC Key Laboratory of Antibody Technique, Department of Microbes and Infection, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China
| | - Hanling Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Lulu Pan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Li Li
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai 200127, China
| | - Kun Song
- State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Tong Qiu
- Department of Obstetrics, Gynecology and Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, 20 Renmin South Road, Chengdu 610041, China
| | - Qiang Pan
- CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Qilong Chen
- CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Guoying Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Yi Zang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Minjia Tan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Jian Zhang
- State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Qintong Li
- Department of Obstetrics, Gynecology and Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, 20 Renmin South Road, Chengdu 610041, China
| | - Xiaoming Wang
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, NHC Key Laboratory of Antibody Technique, Department of Microbes and Infection, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China.
| | - Jun Jiang
- Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China.
| | - Jun Qin
- CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China.
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36
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He J, Cao W, Azeem I, Shao Z. Epigenetics of osteoarthritis: Histones and TGF-β1. Clin Chim Acta 2020; 510:593-598. [PMID: 32795546 DOI: 10.1016/j.cca.2020.08.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 08/05/2020] [Accepted: 08/07/2020] [Indexed: 12/27/2022]
Abstract
Osteoarthritis (OA) is the most common musculoskeletal and joint disorder. However, no disease-modifying therapy for OA is currently available, and the etiology of OA is poorly understood. Epigenetics has emerged as a new and important area of research on OA. Differing from genetics, Epigenetic factors are known to be tissue-specific and highly dynamic, being dependent on environmental stimuli and developmental stages. Therefore, human studies into OA epigenetics are sensitive to confounding and reverse causation. Here, we will review the epigenetic mechanism in OA onset and progression by focusing on the opposing action of two families of enzymes: histone methyltransferases and histone demethylases, such as DOT1L, KDM4B, KDM6A, KDM6B, EZH2, and LSD1. Moreover, the TGF-β1 signaling pathway has proven to be one of the key factors in cartilage and bone formation, and in recent research, was found to initiate and develop OA disease by TGF-β1 overexpression. Besides the introduction of enzymes and TGF-β1 signaling, some special epigenetic regulation mechanisms associated with key transcription factors (e.g. RUNX2, NFAT1, and SOX9) in OA disease are also reviewed here in detail to clarify the OA epigenetic mechanism. The overall understanding of these epigenetic mechanisms underlying the issues will accelerate the development of novel therapeutic strategies for OA.
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Affiliation(s)
- Jianwei He
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; The First Affiliated Hospital, Shihezi University, School of Medicine, Xinjiang, China
| | - Weiwei Cao
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, Shihezi University, School of Medicine, Xinjiang, China
| | - Inayat Azeem
- Office for Education to International Students, School of Medicine, Shihezi University, Xinjiang, China
| | - Zengwu Shao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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37
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Chien YC, Chen JN, Chen YH, Chou RH, Lee HC, Yu YL. Epigenetic Silencing of miR-9 Promotes Migration and Invasion by EZH2 in Glioblastoma Cells. Cancers (Basel) 2020; 12:cancers12071781. [PMID: 32635336 PMCID: PMC7408254 DOI: 10.3390/cancers12071781] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 07/01/2020] [Indexed: 12/14/2022] Open
Abstract
Glioblastoma (GBM) is the most common primary brain tumor in adults. Tumor invasion is the major reason for treatment failure and poor prognosis in GBM. Inhibiting migration and invasion has become an important therapeutic strategy for GBM treatment. Enhancer of zeste homolog 2 (EZH2) and C-X-C motif chemokine receptor 4 (CXCR4) have been determined to have important roles in the occurrence and development of tumors, but the specific relationship between EZH2 and CXCR4 expression in GBM is less well characterized. In this study, we report that EZH2 and CXCR4 were overexpressed in glioma patients. Furthermore, elevated EZH2 and CXCR4 were correlated with shorter disease-free survival. In three human GBM cell lines, EZH2 modulated the expression of miR-9, which directly targeted the oncogenic signaling of CXCR4 in GBM. The ectopic expression of miR-9 dramatically inhibited the migratory capacity of GBM cells in vitro. Taken together, our results indicate that miR-9, functioning as a tumor-suppressive miRNA in GBM, is suppressed through epigenetic silencing by EZH2. Thus, miR-9 may be an attractive target for therapeutic intervention in GBM.
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Affiliation(s)
- Yi-Chung Chien
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; (Y.-C.C.); (J.-N.C.); (Y.-H.C.); (R.-H.C.)
- Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan
| | - Jia-Ni Chen
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; (Y.-C.C.); (J.-N.C.); (Y.-H.C.); (R.-H.C.)
- Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan
| | - Ya-Huey Chen
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; (Y.-C.C.); (J.-N.C.); (Y.-H.C.); (R.-H.C.)
- Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan
- Drug Development Center, China Medical University, Taichung 404, Taiwan
| | - Ruey-Hwang Chou
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; (Y.-C.C.); (J.-N.C.); (Y.-H.C.); (R.-H.C.)
- Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan
- Drug Development Center, China Medical University, Taichung 404, Taiwan
- Department of Biotechnology, Asia University, Taichung 413, Taiwan
| | - Han-Chung Lee
- School of Medicine, College of Medicine, China Medical University, Taichung 404, Taiwan
- Department of Neurosurgery, China Medical University Hospital, Taichung 404, Taiwan
- Correspondence: (H.-C.L.); (Y.-L.Y.); Tel.: +886-4-22052121 (ext. 7911) (Y.-L.Y.)
| | - Yung-Luen Yu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; (Y.-C.C.); (J.-N.C.); (Y.-H.C.); (R.-H.C.)
- Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan
- Drug Development Center, China Medical University, Taichung 404, Taiwan
- Department of Biotechnology, Asia University, Taichung 413, Taiwan
- Correspondence: (H.-C.L.); (Y.-L.Y.); Tel.: +886-4-22052121 (ext. 7911) (Y.-L.Y.)
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38
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Wuputra K, Ku CC, Wu DC, Lin YC, Saito S, Yokoyama KK. Prevention of tumor risk associated with the reprogramming of human pluripotent stem cells. J Exp Clin Cancer Res 2020; 39:100. [PMID: 32493501 PMCID: PMC7268627 DOI: 10.1186/s13046-020-01584-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 04/22/2020] [Indexed: 02/07/2023] Open
Abstract
Human pluripotent embryonic stem cells have two special features: self-renewal and pluripotency. It is important to understand the properties of pluripotent stem cells and reprogrammed stem cells. One of the major problems is the risk of reprogrammed stem cells developing into tumors. To understand the process of differentiation through which stem cells develop into cancer cells, investigators have attempted to identify the key factors that generate tumors in humans. The most effective method for the prevention of tumorigenesis is the exclusion of cancer cells during cell reprogramming. The risk of cancer formation is dependent on mutations of oncogenes and tumor suppressor genes during the conversion of stem cells to cancer cells and on the environmental effects of pluripotent stem cells. Dissecting the processes of epigenetic regulation and chromatin regulation may be helpful for achieving correct cell reprogramming without inducing tumor formation and for developing new drugs for cancer treatment. This review focuses on the risk of tumor formation by human pluripotent stem cells, and on the possible treatment options if it occurs. Potential new techniques that target epigenetic processes and chromatin regulation provide opportunities for human cancer modeling and clinical applications of regenerative medicine.
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Affiliation(s)
- Kenly Wuputra
- Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., San-Ming District, Kaohsiung, 807, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Chia-Chen Ku
- Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., San-Ming District, Kaohsiung, 807, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Deng-Chyang Wu
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Ying-Chu Lin
- School of Dentistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Shigeo Saito
- Waseda University Research Institute for Science and Engineering, Shinjuku, Tokyo, 162-8480, Japan.
- Saito Laboratory of Cell Technology Institute, Yaita, Tochigi, 329-1571, Japan.
| | - Kazunari K Yokoyama
- Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., San-Ming District, Kaohsiung, 807, Taiwan.
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
- Waseda University Research Institute for Science and Engineering, Shinjuku, Tokyo, 162-8480, Japan.
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39
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Harachi M, Masui K, Honda H, Muragaki Y, Kawamata T, Cavenee WK, Mischel PS, Shibata N. Dual Regulation of Histone Methylation by mTOR Complexes Controls Glioblastoma Tumor Cell Growth via EZH2 and SAM. Mol Cancer Res 2020; 18:1142-1152. [PMID: 32366675 DOI: 10.1158/1541-7786.mcr-20-0024] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 03/30/2020] [Accepted: 04/29/2020] [Indexed: 11/16/2022]
Abstract
Epigenetic regulation known for DNA methylation and histone modification is critical for securing proper gene expression and chromosomal function, and its aberration induces various pathologic conditions including cancer. Trimethylation of histone H3 on lysine 27 (H3K27me3) is known to suppress various genes related to cancer cell survival and the level of H3K27me3 may have an influence on tumor progression and malignancy. However, it remains unclear how histone methylation is regulated in response to genetic mutation and microenvironmental cues to facilitate the cancer cell survival. Here, we report a novel mechanism of the specific regulation of H3K27me3 by cooperatively two mTOR complexes, mTORC1 and mTORC2 in human glioblastoma (GBM). Integrated analyses revealed that mTORC1 upregulates the protein expression of enhancer of zeste homolog 2, a main component of polycomb repressive complex 2 which is known as H3K27-specific methyltransferase. The other mTOR complex, mTORC2, regulates production of S-adenosylmethionine, an essential substrate for histone methylation. This cooperative regulation causes H3K27 hypermethylation which subsequently promotes tumor cell survival both in vitro and in vivo xenografted mouse tumor model. These results indicate that activated mTORC1 and mTORC2 complexes cooperatively contribute to tumor progression through specific epigenetic regulation, nominating them as an exploitable therapeutic target against cancer. IMPLICATIONS: A dynamic regulation of histone methylation by mTOR complexes promotes tumor growth in human GBM, but at the same time could be exploitable as a novel therapeutic target against this deadly tumor.
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Affiliation(s)
- Mio Harachi
- Division of Pathological Neuroscience, Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kenta Masui
- Division of Pathological Neuroscience, Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan.
| | - Hiroaki Honda
- Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Institute of Laboratory Animals, Tokyo Women's Medical University, Tokyo, Japan
| | | | | | - Webster K Cavenee
- Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, California
| | - Paul S Mischel
- Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, California
| | - Noriyuki Shibata
- Division of Pathological Neuroscience, Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan
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40
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Nishio H, Buzas DM, Nagano AJ, Iwayama K, Ushio M, Kudoh H. Repressive chromatin modification underpins the long-term expression trend of a perennial flowering gene in nature. Nat Commun 2020; 11:2065. [PMID: 32358518 PMCID: PMC7195410 DOI: 10.1038/s41467-020-15896-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 04/01/2020] [Indexed: 11/17/2022] Open
Abstract
Natural environments require organisms to possess robust mechanisms allowing responses to seasonal trends. In Arabidopsis halleri, the flowering regulator AhgFLC shows upregulation and downregulation phases along with long-term past temperature, but the underlying machinery remains elusive. Here, we investigate the seasonal dynamics of histone modifications, H3K27me3 and H3K4me3, at AhgFLC in a natural population. Our advanced modelling and transplant experiments reveal that H3K27me3-mediated chromatin regulation at AhgFLC provides two essential properties. One is the ability to respond to the long-term temperature trends via bidirectional interactions between H3K27me3 and H3K4me3; the other is the ratchet-like character of the AhgFLC system, i.e. reversible in the entire perennial life cycle but irreversible during the upregulation phase. Furthermore, we show that the long-term temperature trends are locally indexed at AhgFLC in the form of histone modifications. Our study provides a more comprehensive understanding of H3K27me3 function at AhgFLC in a complex natural environment. The flowering regulator FLC shows upregulation and downregulation phases along with long-term past temperature in Arabidopsishalleri. Here, the authors reveal that H3K27me3-mediated chromatin regulation at AhgFLC provides the ability to respond to both the seasonal temperature trends and the perennial life cycle.
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Affiliation(s)
- Haruki Nishio
- Center for Ecological Research, Kyoto University, Otsu, 520-2113, Japan.
| | - Diana M Buzas
- Tsukuba-Plant Innovation Research Center and Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, 305-8572, Japan
| | - Atsushi J Nagano
- Center for Ecological Research, Kyoto University, Otsu, 520-2113, Japan.,Faculty of Agriculture, Ryukoku University, Seta Oe-cho, Otsu, 520-2194, Japan
| | - Koji Iwayama
- Faculty of Data Science, Shiga University, Hikone, 522-8522, Japan.,PRESTO, Japan Science and Technology Agency, Kawaguchi, 332-0012, Japan
| | - Masayuki Ushio
- Center for Ecological Research, Kyoto University, Otsu, 520-2113, Japan.,PRESTO, Japan Science and Technology Agency, Kawaguchi, 332-0012, Japan.,Hakubi Center, Kyoto University, Yoshida-honmachi, Kyoto, 606-8501, Japan
| | - Hiroshi Kudoh
- Center for Ecological Research, Kyoto University, Otsu, 520-2113, Japan.
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41
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Hanan EJ, Liang J, Wang X, Blake RA, Blaquiere N, Staben ST. Monomeric Targeted Protein Degraders. J Med Chem 2020; 63:11330-11361. [DOI: 10.1021/acs.jmedchem.0c00093] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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42
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Tiffen J, Gallagher SJ, Filipp F, Gunatilake D, Emran AA, Cullinane C, Dutton-Register K, Aoude L, Hayward N, Chatterjee A, Rodger EJ, Eccles MR, Hersey P. EZH2 Cooperates with DNA Methylation to Downregulate Key Tumor Suppressors and IFN Gene Signatures in Melanoma. J Invest Dermatol 2020; 140:2442-2454.e5. [PMID: 32360600 DOI: 10.1016/j.jid.2020.02.042] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 02/04/2020] [Accepted: 02/21/2020] [Indexed: 01/14/2023]
Abstract
The histone methylase EZH2 is frequently dysregulated in melanoma and is associated with DNA methylation and silencing of genes involved in tumor suppression. In this study, we used chromatin immunoprecipitation and sequencing to identify key suppressor genes that are silenced by histone methylation in constitutively active EZH2(Y641) mutant melanoma and assessed whether these regions were also sites of DNA methylation. The genes identified were validated by their re-expression after treatment with EZH2 and DNA methyltransferase inhibitors. The expression of putative EZH2 target genes was shown to be highly relevant to the survival of patients with melanoma in clinical datasets. To determine correlates of response to EZH2 inhibitors, we screened a panel of 53 melanoma cell lines for drug sensitivity. We compared RNA sequencing profiles of sensitive to resistant melanoma cells and performed pathway analysis. Sensitivity was associated with strong downregulation of IFN-γ and IFN-α gene signatures that were reversed by treatment with EZH2 inhibitors. This is consistent with EZH2-driven dedifferentiated invasive states associated with treatment resistance and defects in antigen presentation. These results suggest that EZH2 inhibitors may be most effectively targeted to immunologically cold melanoma to both induce direct cytotoxicity and increase immune responses in the context of checkpoint inhibitor immunotherapy.
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Affiliation(s)
- Jessamy Tiffen
- Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia
| | - Stuart J Gallagher
- Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia
| | - Fabian Filipp
- Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, Merced, California, USA
| | - Dilini Gunatilake
- Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia
| | - Abdullah Al Emran
- Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia
| | - Carleen Cullinane
- Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | | | - Lauren Aoude
- The University of Queensland Diamantina Institute, Brisbane, Queensland, Australia
| | - Nick Hayward
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Aniruddha Chatterjee
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
| | - Euan J Rodger
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
| | - Michael R Eccles
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
| | - Peter Hersey
- Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
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43
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Chen J, Zhan C, Zhang L, Zhang L, Liu Y, Zhang Y, Du H, Liang C, Chen X. The Hypermethylation of Foxp3 Promoter Impairs the Function of Treg Cells in EAP. Inflammation 2020; 42:1705-1718. [PMID: 31209730 DOI: 10.1007/s10753-019-01030-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Treg cells are crucial for maintaining immune homeostasis in CP/CPPS, but the molecular mechanisms underlying the modulation of the function of Treg in CP/CPPS remain unclear. The main purpose of this study is to investigate the relationship between immunosuppressive function of Treg and the methylation level of Foxp3 promoter in experimental autoimmune prostatitis (EAP) mouse model. EAP model was induced by subcutaneous injecting prostate-steroid-binding protein (PSBP) and complete Freund's adjuvant with NOD mice. Histological analysis revealed that EAP model was successfully induced. The expression of IFN-γ was increased, and TGF-β was decreased in the serum of EAP, respectively. The percentage of Tregs in splenic lymphocyte was increased in EAP. The suppressive ability of Tregs on Teffs was impaired in EAP. The methylation level of Foxp3 promoter was increased, and the expression of Foxp3 was decreased in EAP. By injection AZA which was DNA-methylation inhibitor into EAP mice, prostate inflammation was alleviated, expressions of TGF-β and Foxp3 were increased, and the suppressive function of Tregs was improved in vitro and in vivo. Thus, we concluded that aberrant increased methylation of Foxp3 promoter in Treg cells leads to the impaired suppressive function of Treg cells, exacerbating autoimmune inflammatory injury in EAP.
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Affiliation(s)
- Jing Chen
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.,Institute of Urology, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Changsheng Zhan
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.,Institute of Urology, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Li Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.,Institute of Urology, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Ligang Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.,Institute of Urology, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Yi Liu
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.,Institute of Urology, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Yong Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.,Institute of Urology, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Hexi Du
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.,Institute of Urology, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Chaozhao Liang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China. .,Institute of Urology, Anhui Medical University, Hefei, China. .,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China.
| | - Xianguo Chen
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China. .,Institute of Urology, Anhui Medical University, Hefei, China. .,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China.
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44
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Du X, Ouyang H. [Correlation between histone methylation level and pathological development of osteoarthritis]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2019; 48:682-687. [PMID: 31955544 PMCID: PMC8800784 DOI: 10.3785/j.issn.1008-9292.2019.12.14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 06/03/2019] [Indexed: 06/10/2023]
Abstract
Osteoarthritis is the most common degenerative cartilage disease. A large number of studies have shown the close association between epigenetics and osteoarthritis. Histone methylation is a type of epigenetic modification, and the link between histone methylation and osteoarthritis has also been revealed. In this article, we summarize the correlation between methylation levels of different histones and osteoarthritis in an attempt to explore the changes and regulation mechanisms of histone methylation in osteoarthritis. It has been shown that there are possible relations between the methylation levels of different amino acids on histone H3 and the pathological development of osteoarthritis; specifically, the rise of methylation level at the lysine 4 would aggravate the pathological development of osteoarthritis, while the the pattern of lysine 9 and 27 would be the opposite. These results indicate the possible existence of a complex network of histone methylation modifications. And the specific regulation of histone methylation levels in different positions may delay or prevent the occurrence and development of osteoarthritis.
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Affiliation(s)
- Xiaotian Du
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Hongwei Ouyang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China
- Zhejiang University-University of Edinburgh Institute, International Campus of Zhejiang University, Haining 314400, Zhejiang Province, China
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45
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Yamashita S, Nanjo S, Rehnberg E, Iida N, Takeshima H, Ando T, Maekita T, Sugiyama T, Ushijima T. Distinct DNA methylation targets by aging and chronic inflammation: a pilot study using gastric mucosa infected with Helicobacter pylori. Clin Epigenetics 2019; 11:191. [PMID: 31829249 PMCID: PMC6907118 DOI: 10.1186/s13148-019-0789-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023] Open
Abstract
Background Aberrant DNA methylation is induced by aging and chronic inflammation in normal tissues. The induction by inflammation is widely recognized as acceleration of age-related methylation. However, few studies addressed target genomic regions and the responsible factors in a genome-wide manner. Here, we analyzed methylation targets by aging and inflammation, taking advantage of the potent methylation induction in human gastric mucosa by Helicobacter pylori infection-triggered inflammation. Results DNA methylation microarray analysis of 482,421 CpG probes, grouped into 270,249 genomic blocks, revealed that high levels of methylation were induced in 44,461 (16.5%) genomic blocks by inflammation, even after correction of the influence of leukocyte infiltration. A total of 61.8% of the hypermethylation was acceleration of age-related methylation while 21.6% was specific to inflammation. Regions with H3K27me3 were frequently hypermethylated both by aging and inflammation. Basal methylation levels were essential for age-related hypermethylation while even regions with little basal methylation were hypermethylated by inflammation. When limited to promoter CpG islands, being a microRNA gene and high basal methylation levels strongly enhanced hypermethylation while H3K27me3 strongly enhanced inflammation-induced hypermethylation. Inflammation was capable of overriding active transcription. In young gastric mucosae, genes with high expression and frequent mutations in gastric cancers were more frequently methylated than in old ones. Conclusions Methylation by inflammation was not simple acceleration of age-related methylation. Targets of aberrant DNA methylation were different between young and old gastric mucosae, and driver genes were preferentially methylated in young gastric mucosa.
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Affiliation(s)
- Satoshi Yamashita
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Sohachi Nanjo
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.,Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Emil Rehnberg
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Naoko Iida
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Hideyuki Takeshima
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Takayuki Ando
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Takao Maekita
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Toshiro Sugiyama
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
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46
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Sanderson SM, Gao X, Dai Z, Locasale JW. Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nat Rev Cancer 2019; 19:625-637. [PMID: 31515518 DOI: 10.1038/s41568-019-0187-8] [Citation(s) in RCA: 322] [Impact Index Per Article: 53.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/24/2019] [Indexed: 01/11/2023]
Abstract
Methionine uptake and metabolism is involved in a host of cellular functions including methylation reactions, redox maintenance, polyamine synthesis and coupling to folate metabolism, thus coordinating nucleotide and redox status. Each of these functions has been shown in many contexts to be relevant for cancer pathogenesis. Intriguingly, the levels of methionine obtained from the diet can have a large effect on cellular methionine metabolism. This establishes a link between nutrition and tumour cell metabolism that may allow for tumour-specific metabolic vulnerabilities that can be influenced by diet. Recently, a number of studies have begun to investigate the molecular and cellular mechanisms that underlie the interaction between nutrition, methionine metabolism and effects on health and cancer.
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Affiliation(s)
- Sydney M Sanderson
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Xia Gao
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Ziwei Dai
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Jason W Locasale
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
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47
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Park JW, Turcan Ş. Epigenetic Reprogramming for Targeting IDH-Mutant Malignant Gliomas. Cancers (Basel) 2019; 11:cancers11101616. [PMID: 31652645 PMCID: PMC6826741 DOI: 10.3390/cancers11101616] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/17/2019] [Accepted: 10/19/2019] [Indexed: 12/24/2022] Open
Abstract
Targeting the epigenome has been considered a compelling treatment modality for several cancers, including gliomas. Nearly 80% of the lower-grade gliomas and secondary glioblastomas harbor recurrent mutations in isocitrate dehydrogenase (IDH). Mutant IDH generates high levels of 2-hydroxyglutarate (2-HG) that inhibit various components of the epigenetic machinery, including histone and DNA demethylases. The encouraging results from current epigenetic therapies in hematological malignancies have reinvigorated the interest in solid tumors and gliomas, both preclinically and clinically. Here, we summarize the recent advancements in epigenetic therapy for lower-grade gliomas and discuss the challenges associated with current treatment options. A particular focus is placed on therapeutic mechanisms underlying favorable outcome with epigenetic-based drugs in basic and translational research of gliomas. This review also highlights emerging bridges to combination treatment with respect to epigenetic drugs. Given that epigenetic therapies, particularly DNA methylation inhibitors, increase tumor immunogenicity and antitumor immune responses, appropriate drug combinations with immune checkpoint inhibitors may lead to improvement of treatment effectiveness of immunotherapy, ultimately leading to tumor cell eradication.
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Affiliation(s)
- Jong-Whi Park
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany.
| | - Şevin Turcan
- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany.
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48
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Paço A, Freitas R. HOX genes as transcriptional and epigenetic regulators during tumorigenesis and their value as therapeutic targets. Epigenomics 2019; 11:1539-1552. [PMID: 31556724 DOI: 10.2217/epi-2019-0090] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Several HOX genes are aberrantly expressed in a wide range of cancers interfering with their development and resistance to treatment. This seems to be often caused by alterations in the methylation profiles of their promoters. The role of HOX gene products in cancer is highly 'tissue specific', relying ultimately on their ability to regulate oncogenes or tumor-suppressor genes, directly as transcriptional regulators or indirectly interfering with the levels of epigenetic regulators. Nowadays, different strategies have been tested the use of HOX genes as therapeutic targets for cancer diagnosis and treatment. Here, we trace the history of the research concerning the involvement of HOX genes in cancer, their connection with epigenetic regulation and their potential use as therapeutic targets.
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Affiliation(s)
- Ana Paço
- Laboratório de Microbiologia do Solo, Instituto de Ciências Agrárias e Ambientais Mediterrânicas (ICAAM), Instituto de Investigação e Formação Avançada (IIFA), Universidade de Évora, 7006-554 Évora, Portugal
| | - Renata Freitas
- I3S - Institute for Innovation & Health Research, University of Porto, 4200-135 Porto, Portugal.,IBMC - Institute for Molecular & Cell Biology, University of Porto, 4200-135 Porto, Portugal.,ICBAS - Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
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49
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Beltran M, Tavares M, Justin N, Khandelwal G, Ambrose J, Foster BM, Worlock KB, Tvardovskiy A, Kunzelmann S, Herrero J, Bartke T, Gamblin SJ, Wilson JR, Jenner RG. G-tract RNA removes Polycomb repressive complex 2 from genes. Nat Struct Mol Biol 2019; 26:899-909. [PMID: 31548724 PMCID: PMC6778522 DOI: 10.1038/s41594-019-0293-z] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 08/05/2019] [Indexed: 12/15/2022]
Abstract
Polycomb Repressive Complex 2 (PRC2) maintains repression of cell type-specific genes but also associates with genes ectopically in cancer. While it is currently unknown how PRC2 is removed from genes, such knowledge would be useful for the targeted reversal of deleterious PRC2 recruitment events. Here, we show that G-tract RNA specifically removes PRC2 from genes in human and mouse cells. PRC2 preferentially binds G-tracts within nascent pre-mRNAs, especially within predicted G-quadruplex structures. G-quadruplex RNA evicts the PRC2 catalytic core from the substrate nucleosome. PRC2 transfers from chromatin to RNA upon gene activation and chromatin-associated G-tract RNA removes PRC2, leading to H3K27me3 depletion from genes. Targeting G-tract RNA to the tumor suppressor gene CDKN2A in malignant rhabdoid tumor cells reactivates the gene and induces senescence. These data support a model in which pre-mRNA evicts PRC2 during gene activation and provides the means to selectively remove PRC2 from specific genes.
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Affiliation(s)
- Manuel Beltran
- UCL Cancer Institute and Cancer Research UK UCL Centre, University College London (UCL), London, UK
| | - Manuel Tavares
- UCL Cancer Institute and Cancer Research UK UCL Centre, University College London (UCL), London, UK
| | | | - Garima Khandelwal
- UCL Cancer Institute and Cancer Research UK UCL Centre, University College London (UCL), London, UK
| | - John Ambrose
- UCL Cancer Institute and Cancer Research UK UCL Centre, University College London (UCL), London, UK.,Genomics England, London, UK
| | - Benjamin M Foster
- Institute of Functional Epigenetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Kaylee B Worlock
- UCL Cancer Institute and Cancer Research UK UCL Centre, University College London (UCL), London, UK
| | - Andrey Tvardovskiy
- Institute of Functional Epigenetics, Helmholtz Zentrum München, Neuherberg, Germany
| | | | - Javier Herrero
- UCL Cancer Institute and Cancer Research UK UCL Centre, University College London (UCL), London, UK
| | - Till Bartke
- Institute of Functional Epigenetics, Helmholtz Zentrum München, Neuherberg, Germany
| | | | | | - Richard G Jenner
- UCL Cancer Institute and Cancer Research UK UCL Centre, University College London (UCL), London, UK.
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50
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Court F, Le Boiteux E, Fogli A, Müller-Barthélémy M, Vaurs-Barrière C, Chautard E, Pereira B, Biau J, Kemeny JL, Khalil T, Karayan-Tapon L, Verrelle P, Arnaud P. Transcriptional alterations in glioma result primarily from DNA methylation-independent mechanisms. Genome Res 2019; 29:1605-1621. [PMID: 31533980 PMCID: PMC6771409 DOI: 10.1101/gr.249219.119] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 08/27/2019] [Indexed: 02/06/2023]
Abstract
In cancer cells, aberrant DNA methylation is commonly associated with transcriptional alterations, including silencing of tumor suppressor genes. However, multiple epigenetic mechanisms, including polycomb repressive marks, contribute to gene deregulation in cancer. To dissect the relative contribution of DNA methylation–dependent and –independent mechanisms to transcriptional alterations at CpG island/promoter-associated genes in cancer, we studied 70 samples of adult glioma, a widespread type of brain tumor, classified according to their isocitrate dehydrogenase (IDH1) mutation status. We found that most transcriptional alterations in tumor samples were DNA methylation–independent. Instead, altered histone H3 trimethylation at lysine 27 (H3K27me3) was the predominant molecular defect at deregulated genes. Our results also suggest that the presence of a bivalent chromatin signature at CpG island promoters in stem cells predisposes not only to hypermethylation, as widely documented, but more generally to all types of transcriptional alterations in transformed cells. In addition, the gene expression strength in healthy brain cells influences the choice between DNA methylation- and H3K27me3-associated silencing in glioma. Highly expressed genes were more likely to be repressed by H3K27me3 than by DNA methylation. Our findings support a model in which altered H3K27me3 dynamics, more specifically defects in the interplay between polycomb protein complexes and the brain-specific transcriptional machinery, is the main cause of transcriptional alteration in glioma cells. Our study provides the first comprehensive description of epigenetic changes in glioma and their relative contribution to transcriptional changes. It may be useful for the design of drugs targeting cancer-related epigenetic defects.
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Affiliation(s)
- Franck Court
- Laboratoire Génétique Reproduction et Développement (GReD), Université Clermont Auvergne, CNRS, INSERM, BP 38, Clermont-Ferrand 63001, France
| | - Elisa Le Boiteux
- Laboratoire Génétique Reproduction et Développement (GReD), Université Clermont Auvergne, CNRS, INSERM, BP 38, Clermont-Ferrand 63001, France
| | - Anne Fogli
- Laboratoire Génétique Reproduction et Développement (GReD), Université Clermont Auvergne, CNRS, INSERM, BP 38, Clermont-Ferrand 63001, France.,Biochemistry and Molecular Biology Department, Clermont-Ferrand Hospital, Clermont-Ferrand 63003, France
| | - Mélanie Müller-Barthélémy
- Laboratoire Génétique Reproduction et Développement (GReD), Université Clermont Auvergne, CNRS, INSERM, BP 38, Clermont-Ferrand 63001, France.,Pathology Department, Jean Perrin Center, Clermont-Ferrand 63011, France
| | - Catherine Vaurs-Barrière
- Laboratoire Génétique Reproduction et Développement (GReD), Université Clermont Auvergne, CNRS, INSERM, BP 38, Clermont-Ferrand 63001, France
| | - Emmanuel Chautard
- Pathology Department, Jean Perrin Center, Clermont-Ferrand 63011, France.,Université Clermont Auvergne, INSERM, U1240 IMoST, Clermont-Ferrand 63011, France
| | - Bruno Pereira
- Biostatistics Department, Délégation à la Recherche Clinique et à l'Innovation, Clermont-Ferrand Hospital, Clermont-Ferrand 63003, France
| | - Julian Biau
- Université Clermont Auvergne, INSERM, U1240 IMoST, Clermont-Ferrand 63011, France.,Radiotherapy Department, Jean Perrin Center, Clermont-Ferrand 63011, France
| | - Jean-Louis Kemeny
- Pathology Department, Université Clermont Auvergne and Clermont-Ferrand Hospital, Clermont-Ferrand 63003, France
| | - Toufic Khalil
- Department of Neurosurgery, Clermont-Ferrand Hospital, Clermont-Ferrand 63003, France
| | - Lucie Karayan-Tapon
- INSERM, U1084, Poitiers 86021, France.,Poitiers University, Poitiers 86000, France.,Department of Cancer Biology, Poitiers Hospital, Poitiers 86021, France
| | - Pierre Verrelle
- INSERM, U1196 CNRS UMR9187, Curie Institute, Orsay 91405, France.,Radiotherapy Department Curie Institute, Paris 75005, France.,Université Clermont Auvergne, Clermont-Ferrand 63000, France
| | - Philippe Arnaud
- Laboratoire Génétique Reproduction et Développement (GReD), Université Clermont Auvergne, CNRS, INSERM, BP 38, Clermont-Ferrand 63001, France
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