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Schäfer Hackenhaar F, Refhagen N, Hagleitner M, van Leeuwen F, Marquart HV, Madsen HO, Landfors M, Osterman P, Schmiegelow K, Flaegstad T, Jónsson Ó, Kanerva J, Abrahamsson J, Heyman M, Norén Nyström U, Hultdin M, Degerman S. CpG island methylator phenotype classification improves risk assessment in pediatric T-cell acute lymphoblastic leukemia. Blood 2025; 145:2161-2178. [PMID: 39841000 DOI: 10.1182/blood.2024026027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 11/21/2024] [Accepted: 12/06/2024] [Indexed: 01/23/2025] Open
Abstract
ABSTRACT Current intensive treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has substantial side effects, highlighting a need for novel biomarkers to improve risk stratification. Canonical biomarkers, such as genetics and immunophenotype, are largely not used in pediatric T-ALL stratification. This study aimed to validate the prognostic relevance of DNA methylation CpG island methylator phenotype (CIMP) risk stratification in 2 pediatric T-ALL patient cohorts: the Nordic Society of Paediatric Haematology (NOPHO) ALL2008 T-ALL study cohort (n = 192) and the Dutch Childhood Oncology Group (DCOG) ALL-10/ALL-11 validation cohorts (n = 156). Both cohorts revealed that combining CIMP classification at diagnosis with measurable residual disease (MRD) at treatment day 29 (D29) or 33 (D33) significantly improved outcome prediction. The poor prognosis subgroup, characterized by CIMP low/D29 or D33 MRD ≥ 0.1%, had a cumulative incidence of relapse (pCIR5yr) of 29% and 23% and overall survival (pOS5yr) of 59.7% and 65.4%, in NOPHO and DCOG, respectively. Conversely, a good prognosis subgroup was also identified representing CIMP high/D29 or D33 MRD < 0.1% with pCIR5yr of 0% and 3.4% and pOS5yr of 98.2% and 94.8%, in NOPHO and DCOG, respectively. For NOPHO, MRD was also evaluated on D15, and the relapse prediction accuracy of CIMP/D29 MRD (0.79) and CIMP/D15 MRD (0.75) classification was comparable, indicating potential for earlier stratification. The evaluation of the biology behind the CIMP subgroups revealed associations with transcriptome profiles, genomic aberrations, and mitotic history, suggesting distinct routes for leukemia development. In conclusion, integrating MRD assessment with the novel CIMP biomarker has the potential to improve risk stratification in pediatric T-ALL and guide future therapeutic decisions.
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Affiliation(s)
| | - Nina Refhagen
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
- Department of Clinical Microbiology, Umeå University, Umeå, Sweden
| | | | - Frank van Leeuwen
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Hanne Vibeke Marquart
- Department of Clinical Immunology, University Hospital Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Hans Ole Madsen
- Department of Clinical Immunology, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Mattias Landfors
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
| | - Pia Osterman
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
| | - Kjeld Schmiegelow
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark
| | - Trond Flaegstad
- Department of Pediatrics, University of Tromsø and University Hospital of North Norway, Tromsø, Norway
| | - Ólafur Jónsson
- Pediatric Hematology-Oncology, Children's Hospital, Landspitali University Hospital, Reykjavik, Iceland
| | - Jukka Kanerva
- New Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Jonas Abrahamsson
- Department of Pediatrics, Institution for Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Mats Heyman
- Department of Pediatrics, University Hospitals, Astrid Lindgrens Barnsjukhus, Stockholm, Sweden
| | | | - Magnus Hultdin
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
| | - Sofie Degerman
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
- Department of Clinical Microbiology, Umeå University, Umeå, Sweden
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Goleij P, Heidari MM, Tabari MAK, Hadipour M, Rezaee A, Javan A, Sanaye PM, Larsen DS, Daglia M, Khan H. Polycomb repressive complex 2 (PRC2) pathway's role in cancer cell plasticity and drug resistance. Funct Integr Genomics 2025; 25:53. [PMID: 40048009 DOI: 10.1007/s10142-025-01563-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 02/17/2025] [Accepted: 02/23/2025] [Indexed: 05/13/2025]
Abstract
Polycomb Repressive Complex 2 (PRC2) is a central regulator of gene expression via the trimethylation of histone H3 on lysine 27. This epigenetic modification plays a crucial role in maintaining cell identity and controlling differentiation, while its dysregulation is closely linked to cancer progression. PRC2 silences tumor suppressor genes, promoting cell proliferation, metastasis, epithelial-mesenchymal transition, and cancer stem cell plasticity. Enhancement of zeste homolog 2 (EZH2) overexpression or gain-of-function mutations have been observed in several cancers, including lymphoma, breast, and prostate cancers, driving aggressive tumor behavior and drug resistance. In addition to EZH2, other PRC2 components, such as embryonic ectoderm development (EED) and suppressor of zeste 12, are essential for complex stability and function. EED, in particular, enhances EZH2 activity and has emerged as a therapeutic target. Inhibitors like MAK683 and EED226 disrupt EED's ability to maintain PRC2 activity, thereby reducing H3K27me3 levels and reactivating tumor suppressor genes. Valemetostat, a dual inhibitor of both EZH2 and EED, has shown promising results in aggressive cancers like diffuse large B-cell lymphoma and small-cell lung cancer, underlining the therapeutic potential of targeting multiple PRC2 components. PRC2's role extends beyond gene repression, as it contributes to metabolic reprogramming in tumors, regulating glycolysis and lipid synthesis to fuel cancer growth. Furthermore, PRC2 is implicated in chemoresistance, particularly by modulating DNA damage response and immune evasion. Tazemetostat, a selective EZH2 inhibitor, has demonstrated significant clinical efficacy in EZH2-mutant cancers, such as non-Hodgkin lymphomas and epithelioid sarcoma. However, the compensatory function of enhancer of zeste homolog 1 (EZH1) in some cancers requires dual inhibition strategies, as seen with agents like UNC1999 and Tulmimetostat, which target both EZH1 and EZH2. Given PRC2's multifaceted role in cancer biology, its inhibition represents a promising avenue for therapeutic intervention. The continued development of PRC2 inhibitors and exploration of their use in combination with standard chemotherapy or immunotherapy has great potential for improving patient outcomes in cancers driven by PRC2 dysregulation.
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Affiliation(s)
- Pouya Goleij
- USERN Office, Kermanshah University of Medical Sciences, Kermanshah, 6715847141, Iran.
- Immunology Board for Transplantation and Cell-Based Therapeutics (Immunotact), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
| | - Mohammad Mahdi Heidari
- Department of Pediatrics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Amin Khazeei Tabari
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Mazandaran, 4815733971, Iran
| | - Mahboube Hadipour
- Department of Biochemistry, School of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, 7919693116, Iran
| | - Aryan Rezaee
- School of Medicine, Iran University of Medical Sciences, Tehran, 1449614535, Iran
| | - Alireza Javan
- School of Medicine, Iran University of Medical Sciences, Tehran, 1449614535, Iran
| | - Pantea Majma Sanaye
- School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, 4513956184, Iran
| | - Danaé S Larsen
- School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, 1010, New Zealand
| | - Maria Daglia
- Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, 80131, Naples, Italy
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang, 212013, China
| | - Haroon Khan
- Department of Pharmacy, Faculty of Chemical and Life Sciences, Abdul Wali Khan University Mardan, Mardan, 23200, Pakistan.
- Department of Pharmacy, Korea University, Sejong, 20019, South Korea.
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O'Geen H, Mihalovits A, Brophy BD, Yang H, Miller MW, Lee CJ, Segal DJ, Tomkova M. De-novo DNA Methylation of Bivalent Promoters Induces Gene Activation through PRC2 Displacement. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.07.636872. [PMID: 39975160 PMCID: PMC11839071 DOI: 10.1101/2025.02.07.636872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Promoter DNA methylation is a key epigenetic mark, commonly associated with gene silencing. However, we noticed that a positive association between promoter DNA methylation and expression is surprisingly common in cancer. Here, we use hit-and-run CRISPR/dCas9 epigenome editing to evaluate how deposition of DNA methylation can regulate gene expression dependent on pre-existing chromatin environment. While the predominant effect of DNA methylation in non-bivalent promoters is gene repression, we show that in bivalent promoters this often leads to gene activation. We demonstrate that gain of DNA methylation leads to reduced MTF2 binding and eviction of H3K27me3, a repressive mark that guards bivalent genes against activation. Our cancer patient data analyses reveal that in cancer, this mechanism likely leads to activation of a large group of transcription factors regulating pluripotency, apoptosis, and senescence signalling. In conclusion, our study uncovers an activating role of DNA methylation in bivalent promoters, with broad implications for cancer and development.
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Zhou W, Reizel Y. On correlative and causal links of replicative epimutations. Trends Genet 2025; 41:60-75. [PMID: 39289103 PMCID: PMC12048181 DOI: 10.1016/j.tig.2024.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 08/20/2024] [Accepted: 08/21/2024] [Indexed: 09/19/2024]
Abstract
The mitotic inheritability of DNA methylation as an epigenetic marker in higher-order eukaryotes has been established for >40 years. The DNA methylome and mitotic division interplay is now considered bidirectional and highly intertwined. Various epigenetic writers, erasers, and modulators shape the perceived replicative methylation dynamics. This Review surveys the principles and complexity of mitotic transmission of DNA methylation, emphasizing the awareness of mitotic aging in analyzing DNA methylation dynamics in development and disease. We reviewed how DNA methylation changes alter mitotic proliferation capacity, implicating age-related diseases like cancer. We link replicative epimutation to stem cell dysfunction, inflammatory response, cancer risks, and epigenetic clocks, discussing the causative role of DNA methylation in health and disease.
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Affiliation(s)
- Wanding Zhou
- Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, PA, 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
| | - Yitzhak Reizel
- Department of Biotechnology and Food Engineering, Technion - Israel Institute of Technology, Haifa, Israel.
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Smith ZD, Hetzel S, Meissner A. DNA methylation in mammalian development and disease. Nat Rev Genet 2025; 26:7-30. [PMID: 39134824 DOI: 10.1038/s41576-024-00760-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2024] [Indexed: 12/15/2024]
Abstract
The DNA methylation field has matured from a phase of discovery and genomic characterization to one seeking deeper functional understanding of how this modification contributes to development, ageing and disease. In particular, the past decade has seen many exciting mechanistic discoveries that have substantially expanded our appreciation for how this generic, evolutionarily ancient modification can be incorporated into robust epigenetic codes. Here, we summarize the current understanding of the distinct DNA methylation landscapes that emerge over the mammalian lifespan and discuss how they interact with other regulatory layers to support diverse genomic functions. We then review the rising interest in alternative patterns found during senescence and the somatic transition to cancer. Alongside advancements in single-cell and long-read sequencing technologies, the collective insights made across these fields offer new opportunities to connect the biochemical and genetic features of DNA methylation to cell physiology, developmental potential and phenotype.
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Affiliation(s)
- Zachary D Smith
- Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA.
| | - Sara Hetzel
- Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Alexander Meissner
- Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.
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6
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Gilardini Montani MS, Benedetti R, Cirone M. Targeting EZH2 in Cancer: Mechanisms, Pathways, and Therapeutic Potential. Molecules 2024; 29:5817. [PMID: 39769907 PMCID: PMC11678268 DOI: 10.3390/molecules29245817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/05/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
Enhancer of zeste homolog 2 (EZH2) is a methyltransferase involved in cell cycle regulation, cell differentiation, and cell death and plays a role in modulating the immune response. Although it mainly functions by catalyzing the tri-methylation of H3 histone on K27 (H3K27), to inhibit the transcription of target genes, EZH2 can directly methylate several transcription factors or form complexes with them, regulating their functions. EZH2 expression/activity is often dysregulated in cancer, contributing to carcinogenesis and immune escape, thereby representing an important target in anti-cancer therapy. This review summarizes some of the mechanisms through which EZH2 regulates the expression and function of tumor suppressor genes and oncogenic molecules such as STAT3, mutant p53, and c-Myc and how it modulates the anti-cancer immune response. The influence of posttranslational modifications on EZH2 activity and stability and the possible strategies leading to its inhibition are also reviewed.
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Affiliation(s)
| | | | - Mara Cirone
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
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Gorse M, Bianchi C, Proudhon C. [Epigenetics and cancer: the role of DNA methylation]. Med Sci (Paris) 2024; 40:925-934. [PMID: 39705563 DOI: 10.1051/medsci/2024180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2024] Open
Abstract
Alterations in DNA methylation profiles are typically found in cancer cells, combining genome-wide hypomethylation with hypermethylation of specific regions, such as CpG islands, which are normally unmethylated. Driving effects in cancer development have been associated with alteration of DNA methylation in certain regions, inducing, for example, the repression of tumor suppressor genes or the activation of oncogenes and retrotransposons. These alterations represent prime candidates for the development of specific markers for the detection, diagnosis and prognosis of cancer. In particular, these markers, distributed along the genome, provide a wealth of information that offers potential for innovation in the field of liquid biopsy, in particular thanks to the emergence of artificial intelligence for diagnostic purposes. This could overcome the limitations related to sensitivities and specificities, which remain too low for the most difficult applications in oncology: the detection of cancers at an early stage, the monitoring of residual disease and the analysis of brain tumors. In addition, targeting the enzymatic processes that control the epigenome offers new therapeutic strategies that could reverse the regulatory anomalies of these altered epigenomes.
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Affiliation(s)
- Marine Gorse
- Université de Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) UMR_S 1085, Rennes, France
| | - Charline Bianchi
- Université de Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) UMR_S 1085, Rennes, France
| | - Charlotte Proudhon
- Université de Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) UMR_S 1085, Rennes, France
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Conway K, Edmiston SN, Vondras A, Reiner A, Corcoran DL, Shen R, Parrish EA, Hao H, Lin L, Kenney JM, Ilelaboye G, Kostrzewa CE, Kuan PF, Busam KJ, Lezcano C, Lee TK, Hernando E, Googe PB, Ollila DW, Moschos S, Gorlov I, Amos CI, Ernstoff MS, Cust AE, Wilmott JS, Scolyer RA, Mann GJ, Vergara IA, Ko J, Rees JR, Yan S, Nagore E, Bosenberg M, Rothberg BG, Osman I, Lee JE, Saenger Y, Bogner P, Thompson CL, Gerstenblith M, Holmen SL, Funchain P, Brunsgaard E, Depcik-Smith ND, Luo L, Boyce T, Orlow I, Begg CB, Berwick M, Thomas NE. DNA Methylation Classes of Stage II and III Primary Melanomas and Their Clinical and Prognostic Significance. JCO Precis Oncol 2024; 8:e2400375. [PMID: 39509669 PMCID: PMC11737429 DOI: 10.1200/po-24-00375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 09/05/2024] [Accepted: 09/20/2024] [Indexed: 11/15/2024] Open
Abstract
PURPOSE Patients with stage II and III cutaneous primary melanoma vary considerably in their risk of melanoma-related death. We explore the ability of methylation profiling to distinguish primary melanoma methylation classes and their associations with clinicopathologic characteristics and survival. MATERIALS AND METHODS InterMEL is a retrospective case-control study that assembled primary cutaneous melanomas from American Joint Committee on Cancer (AJCC) 8th edition stage II and III patients diagnosed between 1998 and 2015 in the United States and Australia. Cases are patients who died of melanoma within 5 years from original diagnosis. Controls survived longer than 5 years without evidence of melanoma recurrence or relapse. Methylation classes, distinguished by consensus clustering of 850K methylation data, were evaluated for their clinicopathologic characteristics, 5-year survival status, and differentially methylated gene sets. RESULTS Among 422 InterMEL melanomas, consensus clustering revealed three primary melanoma methylation classes (MethylClasses): a CpG island methylator phenotype (CIMP) class, an intermediate methylation (IM) class, and a low methylation (LM) class. CIMP and IM were associated with higher AJCC stage (both P = .002), Breslow thickness (CIMP P = .002; IM P = .006), and mitotic index (both P < .001) compared with LM, while IM had higher N stage than CIMP (P = .01) and LM (P = .007). CIMP and IM had a 2-fold higher likelihood of 5-year death from melanoma than LM (CIMP odds ratio [OR], 2.16 [95% CI, 1.18 to 3.96]; IM OR, 2.00 [95% CI, 1.12 to 3.58]) in a multivariable model adjusted for age, sex, log Breslow thickness, ulceration, mitotic index, and N stage. Despite more extensive CpG island hypermethylation in CIMP, CIMP and IM shared similar patterns of differential methylation and gene set enrichment compared with LM. CONCLUSION Melanoma MethylClasses may provide clinical value in predicting 5-year death from melanoma among patients with primary melanoma independent of other clinicopathologic factors.
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Affiliation(s)
- Kathleen Conway
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC
- Department of Dermatology, University of North Carolina, Chapel Hill, NC
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Sharon N. Edmiston
- Department of Dermatology, University of North Carolina, Chapel Hill, NC
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Amanda Vondras
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Allison Reiner
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - David L. Corcoran
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Ronglai Shen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Eloise A. Parrish
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Honglin Hao
- Department of Dermatology, University of North Carolina, Chapel Hill, NC
| | - Lan Lin
- Department of Dermatology, University of North Carolina, Chapel Hill, NC
| | - Jessica M Kenney
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Gbemisola Ilelaboye
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Caroline E. Kostrzewa
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Pei Fen Kuan
- Department of Applied Mathematics and Statistics, State University of New York, Stony Brook, NY
| | - Klaus J. Busam
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Cecilia Lezcano
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Tim K. Lee
- British Columbia Cancer Research Center, Vancouver, BC, Canada
| | - Eva Hernando
- Grossman School of Medicine, New York University, New York, NY
| | - Paul B. Googe
- Department of Dermatology, University of North Carolina, Chapel Hill, NC
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - David W. Ollila
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
- Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Stergios Moschos
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
- Department of Medicine, Division of Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Ivan Gorlov
- Department of Medicine, Baylor Medical Center, Houston, TX
| | | | | | - Anne E. Cust
- The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, Australia
- Melanoma Institute of Australia, The University of Sydney, New South Wales, Australia
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
| | - James S. Wilmott
- Melanoma Institute of Australia, The University of Sydney, New South Wales, Australia
| | - Richard A. Scolyer
- Melanoma Institute of Australia, The University of Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - Graham J. Mann
- Melanoma Institute of Australia, The University of Sydney, New South Wales, Australia
- John Curtin School of Medical Research, Australian National University, ACT 2601, Australia
| | - Ismael A. Vergara
- Melanoma Institute of Australia, The University of Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia
| | | | - Judy R. Rees
- Department of Epidemiology, Dartmouth Medical School, Lebanon NH
| | - Shaofeng Yan
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon NH
| | - Eduardo Nagore
- Instituto Valenciano de Oncologia, Valencia, Spain
- Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain
| | | | | | - Iman Osman
- Grossman School of Medicine, New York University, New York, NY
| | - Jeffrey E. Lee
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Yvonne Saenger
- Columbia University Medical School, New York, NY
- Albert Einstein School of Medicine, New York, NY
| | - Paul Bogner
- Departments of Pathology and Dermatology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Cheryl L. Thompson
- Case Western Reserve University, Cleveland, OH
- Penn State University, Hershey, PA
| | | | - Sheri L. Holmen
- Department of Surgery, University of Utah Health Sciences Center and Huntsman Cancer Institute, Salt Lake City, UT
| | | | - Elise Brunsgaard
- Department of Dermatology, Rush University Medical Center, Chicago, Il
| | | | - Li Luo
- Department of Internal Medicine and the UNM Comprehensive Cancer Center, Albuquerque, NM
| | - Tawny Boyce
- Department of Internal Medicine and the UNM Comprehensive Cancer Center, Albuquerque, NM
| | - Irene Orlow
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Colin B. Begg
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Marianne Berwick
- Department of Internal Medicine and the UNM Comprehensive Cancer Center, Albuquerque, NM
| | - Nancy E. Thomas
- Department of Dermatology, University of North Carolina, Chapel Hill, NC
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
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9
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Esteller M, Dawson MA, Kadoch C, Rassool FV, Jones PA, Baylin SB. The Epigenetic Hallmarks of Cancer. Cancer Discov 2024; 14:1783-1809. [PMID: 39363741 DOI: 10.1158/2159-8290.cd-24-0296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/08/2024] [Accepted: 06/24/2024] [Indexed: 10/05/2024]
Abstract
Cancer is a complex disease in which several molecular and cellular pathways converge to foster the tumoral phenotype. Notably, in the latest iteration of the cancer hallmarks, "nonmutational epigenetic reprogramming" was newly added. However, epigenetics, much like genetics, is a broad scientific area that deserves further attention due to its multiple roles in cancer initiation, progression, and adaptive nature. Herein, we present a detailed examination of the epigenetic hallmarks affected in human cancer, elucidating the pathways and genes involved, and dissecting the disrupted landscapes for DNA methylation, histone modifications, and chromatin architecture that define the disease. Significance: Cancer is a disease characterized by constant evolution, spanning from its initial premalignant stages to the advanced invasive and disseminated stages. It is a pathology that is able to adapt and survive amidst hostile cellular microenvironments and diverse treatments implemented by medical professionals. The more fixed setup of the genetic structure cannot fully provide transformed cells with the tools to survive but the rapid and plastic nature of epigenetic changes is ready for the task. This review summarizes the epigenetic hallmarks that define the ecological success of cancer cells in our bodies.
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Affiliation(s)
- Manel Esteller
- Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
- Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain
- Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
| | - Mark A Dawson
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
- Centre for Cancer Research, University of Melbourne, Melbourne, Australia
| | - Cigall Kadoch
- Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Howard Hughes Medical Institute, Chevy Chase, Maryland
| | - Feyruz V Rassool
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Peter A Jones
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan
| | - Stephen B Baylin
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan
- Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
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10
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Haefliger S, Chervova O, Davies C, Loh C, Tirabosco R, Amary F, Pillay N, Horvath S, Beck S, Flanagan AM, Lyskjær I. Epigenetic age acceleration is a distinctive trait of epithelioid sarcoma with potential therapeutic implications. GeroScience 2024; 46:5203-5209. [PMID: 38879847 PMCID: PMC11336154 DOI: 10.1007/s11357-024-01156-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 04/05/2024] [Indexed: 08/22/2024] Open
Abstract
Recently, DNA methylation clocks have been proven to be precise age predictors, and the application of these clocks in cancer tissue has revealed a global age acceleration in a majority of cancer subtypes when compared to normal tissue from the same individual. The polycomb repressor complex 2 plays a pivotal role in the aging process, and its targets have been shown to be enriched in CpG sites that gain methylation with age. This complex is further regulated by the chromatin remodeling complex SWItch/Sucrose Non-Fermentable and its core subunit, notably the tumor suppressor gene SMARCB1, which under physiological conditions inhibits the activity of the polycomb repressor complex 2. Hence, the loss of function of core members of the SWItch/sucrose non-fermentable complex, such as the tumor suppressor gene SMARCB1, results in increased activity of polycomb repressor complex 2 and interferes with the aging process. SMARCB1-deficient neoplasms represent a family of rare tumors, including amongst others malignant rhabdoid tumors, atypical teratoid and rhabdoid tumors, and epithelioid sarcomas. As aging pathways have recently been proposed as therapeutic targets for various cancer types, these tumors represent candidates for testing such treatments. Here, by deriving epigenetic age scores from more than 1000 tumor samples, we identified epigenetic age acceleration as a hallmark feature of epithelioid sarcoma. This observation highlights the potential of targeting aging pathways as an innovative treatment approach for patients with epithelioid sarcoma.
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Affiliation(s)
- Simon Haefliger
- Research Department of Pathology, University College London, UCL Cancer Institute, London, UK
- Bone Tumor Reference Centre, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
- Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, London, UK
| | - Olga Chervova
- Medical Genomics Research Group, University College London, UCL Cancer Institute, London, UK
| | - Christopher Davies
- Research Department of Pathology, University College London, UCL Cancer Institute, London, UK
- Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, London, UK
| | - Chet Loh
- Altos Labs, Cambridge Institute of Science, Cambridge, UK
| | - Roberto Tirabosco
- Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, London, UK
| | - Fernanda Amary
- Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, London, UK
| | - Nischalan Pillay
- Research Department of Pathology, University College London, UCL Cancer Institute, London, UK
- Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, London, UK
| | - Steve Horvath
- Altos Labs, Cambridge Institute of Science, Cambridge, UK
| | - Stephan Beck
- Medical Genomics Research Group, University College London, UCL Cancer Institute, London, UK
| | - Adrienne M Flanagan
- Research Department of Pathology, University College London, UCL Cancer Institute, London, UK.
- Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, London, UK.
| | - Iben Lyskjær
- Research Department of Pathology, University College London, UCL Cancer Institute, London, UK
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
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11
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Gretarsson KH, Abini-Agbomson S, Gloor SL, Weinberg DN, McCuiston JL, Kumary VUS, Hickman AR, Sahu V, Lee R, Xu X, Lipieta N, Flashner S, Adeleke OA, Popova IK, Taylor HF, Noll K, Windham CL, Maryanski DN, Venters BJ, Nakagawa H, Keogh MC, Armache KJ, Lu C. Cancer-associated DNA hypermethylation of Polycomb targets requires DNMT3A dual recognition of histone H2AK119 ubiquitination and the nucleosome acidic patch. SCIENCE ADVANCES 2024; 10:eadp0975. [PMID: 39196936 PMCID: PMC11352909 DOI: 10.1126/sciadv.adp0975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 07/24/2024] [Indexed: 08/30/2024]
Abstract
During tumor development, promoter CpG islands that are normally silenced by Polycomb repressive complexes (PRCs) become DNA-hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) [DNMT(s)] catalyze CpG methylation at PRC-regulated regions remains unclear. Here, we report a cryo-electron microscopy structure of the DNMT3A long isoform (DNMT3A1) amino-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine-119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 amino terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Further, aberrant redistribution of DNMT3A1 to Polycomb target genes recapitulates the cancer-associated DNA hypermethylation signature and inhibits their transcriptional activation during cell differentiation. This effect is rescued by disruption of the DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for mediating promoter CpG island DNA hypermethylation, a major molecular hallmark of cancer.
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Affiliation(s)
- Kristjan H. Gretarsson
- Department of Genetics and Development and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Stephen Abini-Agbomson
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | | | - Daniel N. Weinberg
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | | | | | | | - Varun Sahu
- Department of Genetics and Development and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Rachel Lee
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Xinjing Xu
- Department of Genetics and Development and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Natalie Lipieta
- Department of Genetics and Development and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Samuel Flashner
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY 10032, USA
| | | | | | | | | | | | | | | | - Hiroshi Nakagawa
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY 10032, USA
| | | | - Karim-Jean Armache
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Chao Lu
- Department of Genetics and Development and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA
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12
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Rajan PK, Udoh UAS, Finley R, Pierre SV, Sanabria J. The Biological Clock of Liver Metabolism in Metabolic Dysfunction-Associated Steatohepatitis Progression to Hepatocellular Carcinoma. Biomedicines 2024; 12:1961. [PMID: 39335475 PMCID: PMC11428469 DOI: 10.3390/biomedicines12091961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/12/2024] [Accepted: 08/19/2024] [Indexed: 09/30/2024] Open
Abstract
Circadian rhythms are endogenous behavioral or physiological cycles that are driven by a daily biological clock that persists in the absence of geophysical or environmental temporal cues. Circadian rhythm-related genes code for clock proteins that rise and fall in rhythmic patterns driving biochemical signals of biological processes from metabolism to physiology and behavior. Clock proteins have a pivotal role in liver metabolism and homeostasis, and their disturbances are implicated in various liver disease processes. Encoded genes play critical roles in the initiation and progression of metabolic dysfunction-associated steatohepatitis (MASH) to hepatocellular carcinoma (HCC) and their proteins may become diagnostic markers as well as therapeutic targets. Understanding molecular and metabolic mechanisms underlying circadian rhythms will aid in therapeutic interventions and may have broader clinical applications. The present review provides an overview of the role of the liver's circadian rhythm in metabolic processes in health and disease, emphasizing MASH progression and the oncogenic associations that lead to HCC.
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Affiliation(s)
- Pradeep Kumar Rajan
- Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA
- Department of Surgery, School of Medicine, Marshall University, Huntington, WV 25701, USA
| | - Utibe-Abasi S Udoh
- Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA
- Department of Surgery, School of Medicine, Marshall University, Huntington, WV 25701, USA
| | - Robert Finley
- Department of Surgery, School of Medicine, Marshall University, Huntington, WV 25701, USA
| | - Sandrine V Pierre
- Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA
| | - Juan Sanabria
- Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA
- Department of Surgery, School of Medicine, Marshall University, Huntington, WV 25701, USA
- Department of Nutrition and Metabolomic Core Facility, School of Medicine, Case Western Reserve University, Cleveland, OH 44100, USA
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13
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Jain N, Li JL, Tong L, Jasmine F, Kibriya MG, Demanelis K, Oliva M, Chen LS, Pierce BL. DNA methylation correlates of chronological age in diverse human tissue types. Epigenetics Chromatin 2024; 17:25. [PMID: 39118140 PMCID: PMC11308253 DOI: 10.1186/s13072-024-00546-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 06/15/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND While the association of chronological age with DNA methylation (DNAm) in whole blood has been extensively studied, the tissue-specificity of age-related DNAm changes remains an active area of research. Studies investigating the association of age with DNAm in tissues such as brain, skin, immune cells, fat, and liver have identified tissue-specific and non-specific effects, thus, motivating additional studies of diverse human tissue and cell types. RESULTS Here, we performed an epigenome-wide association study, leveraging DNAm data (Illumina EPIC array) from 961 tissue samples representing 9 tissue types (breast, lung, colon, ovary, prostate, skeletal muscle, testis, whole blood, and kidney) from the Genotype-Tissue Expression (GTEx) project. We identified age-associated CpG sites (false discovery rate < 0.05) in 8 tissues (all except skeletal muscle, n = 47). This included 162,002 unique hypermethylated and 90,626 hypomethylated CpG sites across all tissue types, with 130,137 (80%) hypermethylated CpGs and 74,703 (82%) hypomethylated CpG sites observed in a single tissue type. While the majority of age-associated CpG sites appeared tissue-specific, the patterns of enrichment among genomic features, such as chromatin states and CpG islands, were similar across most tissues, suggesting common mechanisms underlying cellular aging. Consistent with previous findings, we observed that hypermethylated CpG sites are enriched in regions with repressed polycomb signatures and CpG islands, while hypomethylated CpG sites preferentially occurred in non-CpG islands and enhancers. To gain insights into the functional effects of age-related DNAm changes, we assessed the correlation between DNAm and local gene expression changes to identify age-related expression quantitative trait methylation (age-eQTMs). We identified several age-eQTMs present in multiple tissue-types, including in the CDKN2A, HENMT1, and VCWE regions. CONCLUSION Overall, our findings will aid future efforts to develop biomarkers of aging and understand mechanisms of aging in diverse human tissue types.
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Affiliation(s)
- Niyati Jain
- Department of Public Health Sciences, University of Chicago, Chicago, IL, 60637, USA
- Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, IL, 60637, USA
| | - James L Li
- Department of Public Health Sciences, University of Chicago, Chicago, IL, 60637, USA
- Interdisciplinary Scientist Training Program, University of Chicago, Chicago, IL, 60637, USA
| | - Lin Tong
- Department of Public Health Sciences, University of Chicago, Chicago, IL, 60637, USA
| | - Farzana Jasmine
- Institute for Population and Precision Health (IPPH), Biological Sciences Division, University of Chicago, Chicago, IL, 60637, USA
| | - Muhammad G Kibriya
- Department of Public Health Sciences, University of Chicago, Chicago, IL, 60637, USA
| | - Kathryn Demanelis
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, 15232, USA
| | - Meritxell Oliva
- Department of Public Health Sciences, University of Chicago, Chicago, IL, 60637, USA
- Genomics Research Center, AbbVie, North Chicago, IL, 60064, USA
| | - Lin S Chen
- Department of Public Health Sciences, University of Chicago, Chicago, IL, 60637, USA
| | - Brandon L Pierce
- Department of Public Health Sciences, University of Chicago, Chicago, IL, 60637, USA.
- Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA.
- Comprehensive Cancer Center, University of Chicago, Chicago, IL, 60637, USA.
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14
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Moqri M, Cipriano A, Simpson DJ, Rasouli S, Murty T, de Jong TA, Nachun D, de Sena Brandine G, Ying K, Tarkhov A, Aberg KA, van den Oord E, Zhou W, Smith A, Mackall C, Gladyshev VN, Horvath S, Snyder MP, Sebastiano V. PRC2-AgeIndex as a universal biomarker of aging and rejuvenation. Nat Commun 2024; 15:5956. [PMID: 39009581 PMCID: PMC11250797 DOI: 10.1038/s41467-024-50098-2] [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: 02/27/2024] [Accepted: 07/01/2024] [Indexed: 07/17/2024] Open
Abstract
DNA methylation (DNAm) is one of the most reliable biomarkers of aging across mammalian tissues. While the age-dependent global loss of DNAm has been well characterized, DNAm gain is less characterized. Studies have demonstrated that CpGs which gain methylation with age are enriched in Polycomb Repressive Complex 2 (PRC2) targets. However, whole-genome examination of all PRC2 targets as well as determination of the pan-tissue or tissue-specific nature of these associations is lacking. Here, we show that low-methylated regions (LMRs) which are highly bound by PRC2 in embryonic stem cells (PRC2 LMRs) gain methylation with age in all examined somatic mitotic cells. We estimated that this epigenetic change represents around 90% of the age-dependent DNAm gain genome-wide. Therefore, we propose the "PRC2-AgeIndex," defined as the average DNAm in PRC2 LMRs, as a universal biomarker of cellular aging in somatic cells which can distinguish the effect of different anti-aging interventions.
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Affiliation(s)
- Mahdi Moqri
- Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, USA
- Department of Obstetrics & Gynecology, School of Medicine, Stanford University, Stanford, CA, USA
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA
| | - Andrea Cipriano
- Department of Obstetrics & Gynecology, School of Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA, USA
| | - Daniel J Simpson
- Department of Obstetrics & Gynecology, School of Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA, USA
| | - Sajede Rasouli
- Department of Obstetrics & Gynecology, School of Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA, USA
| | - Tara Murty
- Center for Cancer Cell Therapy, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA, USA
| | - Tineke Anna de Jong
- Department of Obstetrics & Gynecology, School of Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA, USA
| | - Daniel Nachun
- Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USA
| | | | - Kejun Ying
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Andrei Tarkhov
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Karolina A Aberg
- Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Edwin van den Oord
- Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Wanding Zhou
- Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Andrew Smith
- Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
| | - Crystal Mackall
- Center for Cancer Cell Therapy, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA, USA
- Department of Pediatrics, Division of Hematology and Oncology, School of Medicine, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Stem Cell Transplantation and Cell Therapy, School of Medicine, Stanford University, Stanford, CA, USA
| | - Vadim N Gladyshev
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Steve Horvath
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Altos Labs, San Diego, CA, USA
| | - Michael P Snyder
- Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA.
- Center for Genomics and Personalized Medicine, Stanford University, Stanford, CA, USA.
| | - Vittorio Sebastiano
- Department of Obstetrics & Gynecology, School of Medicine, Stanford University, Stanford, CA, USA.
- Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA, USA.
- Stanford Maternal & Child Health Research Institute, Stanford University, Stanford, CA, USA.
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15
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Corveleyn L, Sen P, Adams P, Sidoli S. Linking Aging to Cancer: The Role of Chromatin Biology. J Gerontol A Biol Sci Med Sci 2024; 79:glae133. [PMID: 38761362 PMCID: PMC11170291 DOI: 10.1093/gerona/glae133] [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: 02/20/2024] [Indexed: 05/20/2024] Open
Abstract
Epigenetic changes have been established to be a hallmark of aging, which implies that aging science requires collaborating with the field of chromatin biology. DNA methylation patterns, changes in relative abundance of histone post-translational modifications, and chromatin remodeling are the central players in modifying chromatin structure. Aging is commonly associated with an overall increase in chromatin instability, loss of homeostasis, and decondensation. However, numerous publications have highlighted that the link between aging and chromatin changes is not nearly as linear as previously expected. This complex interplay of these epigenetic elements during the lifetime of an organism likely contributes to cellular senescence, genomic instability, and disease susceptibility. Yet, the causal links between these phenomena still need to be fully unraveled. In this perspective article, we discuss potential future directions of aging chromatin biology.
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Affiliation(s)
- Laura Corveleyn
- Laboratory of Pharmaceutical Biotechnology, Department of Pharmaceutics, Ghent University, Ghent, Belgium
| | - Payel Sen
- Laboratory of Genetics and Genomics, National Institute on Aging, Baltimore, Maryland, USA
| | - Peter Adams
- Sanford Burnham Prebys Medical Discovery Institute, San Diego, California, USA
| | - Simone Sidoli
- Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, USA
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16
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Yokomizo T, Oshima M, Iwama A. Epigenetics of hematopoietic stem cell aging. Curr Opin Hematol 2024; 31:207-216. [PMID: 38640057 DOI: 10.1097/moh.0000000000000818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2024]
Abstract
PURPOSE OF REVIEW The development of new antiaging medicines is of great interest to the current elderly and aging population. Aging of the hematopoietic system is attributed to the aging of hematopoietic stem cells (HSCs), and epigenetic alterations are the key effectors driving HSC aging. Understanding the epigenetics of HSC aging holds promise of providing new insights for combating HSC aging and age-related hematological malignancies. RECENT FINDINGS Aging is characterized by the progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. During aging, the HSCs undergo both quantitative and qualitative changes. These functional changes in HSCs cause dysregulated hematopoiesis, resulting in anemia, immune dysfunction, and an increased risk of hematological malignancies. Various cell-intrinsic and cell-extrinsic effectors influencing HSC aging have also been identified. Epigenetic alterations are one such mechanism. SUMMARY Cumulative epigenetic alterations in aged HSCs affect their fate, leading to aberrant self-renewal, differentiation, and function of aged HSCs. In turn, these factors provide an opportunity for aged HSCs to expand by modulating their self-renewal and differentiation balance, thereby contributing to the development of hematological malignancies.
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Affiliation(s)
- Takako Yokomizo
- Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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17
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Blanchett R, Lau KH, Pfeifer GP. Homeobox and Polycomb target gene methylation in human solid tumors. Sci Rep 2024; 14:13912. [PMID: 38886487 PMCID: PMC11183203 DOI: 10.1038/s41598-024-64569-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 06/11/2024] [Indexed: 06/20/2024] Open
Abstract
DNA methylation is an epigenetic mark that plays an important role in defining cancer phenotypes, with global hypomethylation and focal hypermethylation at CpG islands observed in tumors. These methylation marks can also be used to define tumor types and provide an avenue for biomarker identification. The homeobox gene class is one that has potential for this use, as well as other genes that are Polycomb Repressive Complex 2 targets. To begin to unravel this relationship, we performed a pan-cancer DNA methylation analysis using sixteen Illumina HM450k array datasets from TCGA, delving into cancer-specific qualities and commonalities between tumor types with a focus on homeobox genes. Our comparisons of tumor to normal samples suggest that homeobox genes commonly harbor significant hypermethylated differentially methylated regions. We identified two homeobox genes, HOXA3 and HOXD10, that are hypermethylated in all 16 cancer types. Furthermore, we identified several potential homeobox gene biomarkers from our analysis that are uniquely methylated in only one tumor type and that could be used as screening tools in the future. Overall, our study demonstrates unique patterns of DNA methylation in multiple tumor types and expands on the interplay between the homeobox gene class and oncogenesis.
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Affiliation(s)
- Reid Blanchett
- Department of Epigenetics, Van Andel Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, 49503, USA
| | - Kin H Lau
- Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Gerd P Pfeifer
- Department of Epigenetics, Van Andel Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, 49503, USA.
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18
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Shi TH, Sugishita H, Gotoh Y. Crosstalk within and beyond the Polycomb repressive system. J Cell Biol 2024; 223:e202311021. [PMID: 38506728 PMCID: PMC10955045 DOI: 10.1083/jcb.202311021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 03/01/2024] [Accepted: 03/04/2024] [Indexed: 03/21/2024] Open
Abstract
The development of multicellular organisms depends on spatiotemporally controlled differentiation of numerous cell types and their maintenance. To generate such diversity based on the invariant genetic information stored in DNA, epigenetic mechanisms, which are heritable changes in gene function that do not involve alterations to the underlying DNA sequence, are required to establish and maintain unique gene expression programs. Polycomb repressive complexes represent a paradigm of epigenetic regulation of developmentally regulated genes, and the roles of these complexes as well as the epigenetic marks they deposit, namely H3K27me3 and H2AK119ub, have been extensively studied. However, an emerging theme from recent studies is that not only the autonomous functions of the Polycomb repressive system, but also crosstalks of Polycomb with other epigenetic modifications, are important for gene regulation. In this review, we summarize how these crosstalk mechanisms have improved our understanding of Polycomb biology and how such knowledge could help with the design of cancer treatments that target the dysregulated epigenome.
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Affiliation(s)
- Tianyi Hideyuki Shi
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Hiroki Sugishita
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
- International Research Center for Neurointelligence, The University of Tokyo, Tokyo, Japan
| | - Yukiko Gotoh
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
- International Research Center for Neurointelligence, The University of Tokyo, Tokyo, Japan
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19
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Teschendorff AE. On epigenetic stochasticity, entropy and cancer risk. Philos Trans R Soc Lond B Biol Sci 2024; 379:20230054. [PMID: 38432318 PMCID: PMC10909509 DOI: 10.1098/rstb.2023.0054] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 09/26/2023] [Indexed: 03/05/2024] Open
Abstract
Epigenetic changes are known to accrue in normal cells as a result of ageing and cumulative exposure to cancer risk factors. Increasing evidence points towards age-related epigenetic changes being acquired in a quasi-stochastic manner, and that they may play a causal role in cancer development. Here, I describe the quasi-stochastic nature of DNA methylation (DNAm) changes in ageing cells as well as in normal cells at risk of neoplastic transformation, discussing the implications of this stochasticity for developing cancer risk prediction strategies, and in particular, how it may require a conceptual paradigm shift in how we select cancer risk markers. I also describe the mounting evidence that a significant proportion of DNAm changes in ageing and cancer development are related to cell proliferation, reflecting tissue-turnover and the opportunity this offers for predicting cancer risk via the development of epigenetic mitotic-like clocks. Finally, I describe how age-associated DNAm changes may be causally implicated in cancer development via an irreversible suppression of tissue-specific transcription factors that increases epigenetic and transcriptomic entropy, promoting a more plastic yet aberrant cancer stem-cell state. This article is part of a discussion meeting issue 'Causes and consequences of stochastic processes in development and disease'.
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Affiliation(s)
- Andrew E. Teschendorff
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, People's Republic of China
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20
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Chomiak AA, Tiedemann RL, Liu Y, Kong X, Cui Y, Wiseman AK, Thurlow KE, Cornett EM, Topper MJ, Baylin SB, Rothbart SB. Select EZH2 inhibitors enhance viral mimicry effects of DNMT inhibition through a mechanism involving NFAT:AP-1 signaling. SCIENCE ADVANCES 2024; 10:eadk4423. [PMID: 38536911 PMCID: PMC10971413 DOI: 10.1126/sciadv.adk4423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 02/21/2024] [Indexed: 04/05/2024]
Abstract
DNA methyltransferase inhibitor (DNMTi) efficacy in solid tumors is limited. Colon cancer cells exposed to DNMTi accumulate lysine-27 trimethylation on histone H3 (H3K27me3). We propose this Enhancer of Zeste Homolog 2 (EZH2)-dependent repressive modification limits DNMTi efficacy. Here, we show that low-dose DNMTi treatment sensitizes colon cancer cells to select EZH2 inhibitors (EZH2is). Integrative epigenomic analysis reveals that DNMTi-induced H3K27me3 accumulates at genomic regions poised with EZH2. Notably, combined EZH2i and DNMTi alters the epigenomic landscape to transcriptionally up-regulate the calcium-induced nuclear factor of activated T cells (NFAT):activating protein 1 (AP-1) signaling pathway. Blocking this pathway limits transcriptional activating effects of these drugs, including transposable element and innate immune response gene expression involved in viral defense. Analysis of primary human colon cancer specimens reveals positive correlations between DNMTi-, innate immune response-, and calcium signaling-associated transcription profiles. Collectively, we show that compensatory EZH2 activity limits DNMTi efficacy in colon cancer and link NFAT:AP-1 signaling to epigenetic therapy-induced viral mimicry.
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Affiliation(s)
- Alison A. Chomiak
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | | | - Yanqing Liu
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Xiangqian Kong
- Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Ying Cui
- Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Ashley K. Wiseman
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Kate E. Thurlow
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Evan M. Cornett
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indiana University, Indianapolis, IN 46202, USA
| | - Michael J. Topper
- Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Stephen B. Baylin
- Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Scott B. Rothbart
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
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21
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Gretarsson KH, Abini-Agbomson S, Gloor SL, Weinberg DN, McCuiston JL, Kumary VUS, Hickman AR, Sahu V, Lee R, Xu X, Lipieta N, Flashner S, Adeleke OA, Popova IK, Taylor HF, Noll K, Windham CL, Maryanski DN, Venters BJ, Nakagawa H, Keogh MC, Armache KJ, Lu C. Cancer-associated DNA Hypermethylation of Polycomb Targets Requires DNMT3A Dual Recognition of Histone H2AK119 Ubiquitination and the Nucleosome Acidic Patch. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.18.585588. [PMID: 38562823 PMCID: PMC10983913 DOI: 10.1101/2024.03.18.585588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
During tumor development, promoter CpG islands (CGIs) that are normally silenced by Polycomb repressive complexes (PRCs) become DNA hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) catalyze CpG methylation at PRC-regulated regions remains unclear. Here we report a cryo-EM structure of the DNMT3A long isoform (DNMT3A1) N-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine 119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 N-terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Furthermore, aberrant redistribution of DNMT3A1 to Polycomb target genes inhibits their transcriptional activation during cell differentiation and recapitulates the cancer-associated DNA hypermethylation signature. This effect is rescued by disruption of the DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for countering promoter CGI DNA hypermethylation, a major molecular hallmark of cancer.
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22
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Wang W, Li D, Xu Q, Cheng J, Yu Z, Li G, Qiao S, Pan J, Wang H, Shi J, Zheng T, Sui G. G-quadruplexes promote the motility in MAZ phase-separated condensates to activate CCND1 expression and contribute to hepatocarcinogenesis. Nat Commun 2024; 15:1045. [PMID: 38316778 PMCID: PMC10844655 DOI: 10.1038/s41467-024-45353-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 01/22/2024] [Indexed: 02/07/2024] Open
Abstract
G-quadruplexes (G4s) can recruit transcription factors to activate gene expression, but detailed mechanisms remain enigmatic. Here, we demonstrate that G4s in the CCND1 promoter propel the motility in MAZ phase-separated condensates and subsequently activate CCND1 transcription. Zinc finger (ZF) 2 of MAZ is a responsible for G4 binding, while ZF3-5, but not a highly disordered region, is critical for MAZ condensation. MAZ nuclear puncta overlaps with signals of G4s and various coactivators including BRD4, MED1, CDK9 and active RNA polymerase II, as well as gene activation histone markers. MAZ mutants lacking either G4 binding or phase separation ability did not form nuclear puncta, and showed deficiencies in promoting hepatocellular carcinoma cell proliferation and xenograft tumor formation. Overall, we unveiled that G4s recruit MAZ to the CCND1 promoter and facilitate the motility in MAZ condensates that compartmentalize coactivators to activate CCND1 expression and subsequently exacerbate hepatocarcinogenesis.
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Affiliation(s)
- Wenmeng Wang
- College of Life Science, Northeast Forestry University, Harbin, 150040, China
| | - Dangdang Li
- College of Life Science, Northeast Forestry University, Harbin, 150040, China.
| | - Qingqing Xu
- College of Life Science, Northeast Forestry University, Harbin, 150040, China
| | - Jiahui Cheng
- College of Life Science, Northeast Forestry University, Harbin, 150040, China
| | - Zhiwei Yu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Guangyue Li
- College of Life Science, Northeast Forestry University, Harbin, 150040, China
| | - Shiyao Qiao
- College of Life Science, Northeast Forestry University, Harbin, 150040, China
| | - Jiasong Pan
- College of Life Science, Northeast Forestry University, Harbin, 150040, China
| | - Hao Wang
- College of Life Science, Northeast Forestry University, Harbin, 150040, China
| | - Jinming Shi
- College of Life Science, Northeast Forestry University, Harbin, 150040, China
| | - Tongsen Zheng
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
- Key Laboratory of Molecular Oncology of Heilongjiang Province, Harbin, China
| | - Guangchao Sui
- College of Life Science, Northeast Forestry University, Harbin, 150040, China.
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23
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Abstract
Lymphoid neoplasms represent a heterogeneous group of disease entities and subtypes with markedly different molecular and clinical features. Beyond genetic alterations, lymphoid tumors also show widespread epigenomic changes. These severely affect the levels and distribution of DNA methylation, histone modifications, chromatin accessibility, and three-dimensional genome interactions. DNA methylation stands out as a tracer of cell identity and memory, as B cell neoplasms show epigenetic imprints of their cellular origin and proliferative history, which can be quantified by an epigenetic mitotic clock. Chromatin-associated marks are informative to uncover altered regulatory regions and transcription factor networks contributing to the development of distinct lymphoid tumors. Tumor-intrinsic epigenetic and genetic aberrations cooperate and interact with microenvironmental cells to shape the transcriptome at different phases of lymphoma evolution, and intraclonal heterogeneity can now be characterized by single-cell profiling. Finally, epigenetics offers multiple clinical applications, including powerful diagnostic and prognostic biomarkers as well as therapeutic targets.
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Affiliation(s)
- Martí Duran-Ferrer
- Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain;
| | - José Ignacio Martín-Subero
- Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain;
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona, Spain
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24
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Wu K, Sun Q, Liu D, Lu J, Wen D, Zang X, Gao L. Alternative Splicing Landscape of Head and Neck Squamous Cell Carcinoma. Technol Cancer Res Treat 2024; 23:15330338241272051. [PMID: 39113534 PMCID: PMC11307358 DOI: 10.1177/15330338241272051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 06/16/2024] [Accepted: 06/24/2024] [Indexed: 08/10/2024] Open
Abstract
Head and neck malignancies are a significant global health concern, with head and neck squamous cell carcinoma (HNSCC) being the sixth most common cancer worldwide accounting for > 90% of cases. In recent years, there has been growing recognition of the potential role of alternative splicing (AS) in the etiology of cancer. Increasing evidence suggests that AS is associated with various aspects of cancer progression, including tumor occurrence, invasion, metastasis, and drug resistance. Additionally, AS is involved in shaping the tumor microenvironment, which plays a crucial role in tumor development and response to therapy. AS can influence the expression of factors involved in angiogenesis, immune response, and extracellular matrix remodeling, all of which contribute to the formation of a supportive microenvironment for tumor growth. Exploring the mechanism of AS events in HNSCC could provide insights into the development and progression of this cancer, as well as its interaction with the tumor microenvironment. Understanding how AS contributes to the molecular changes in HNSCC cells and influences the tumor microenvironment could lead to the identification of new therapeutic targets. Targeted chemotherapy and immunotherapy strategies tailored to the specific AS patterns in HNSCC could potentially improve treatment outcomes and reduce side effects. This review explores the concept, types, processes, and technological advancements of AS, focusing on its role in the initiation, progression, treatment, and prognosis of HNSCC.
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Affiliation(s)
- Kehan Wu
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, PR China
| | - Qianhui Sun
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, PR China
| | - Dongxu Liu
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, PR China
| | - Jiayi Lu
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, PR China
| | - Deyu Wen
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, PR China
| | - Xiyan Zang
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, PR China
| | - Li Gao
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, PR China
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25
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Panzeri I, Fagnocchi L, Apostle S, Tompkins M, Wolfrum E, Madaj Z, Hostetter G, Liu Y, Schaefer K, Chih-Hsiang Y, Bergsma A, Drougard A, Dror E, Chandler D, Schramek D, Triche TJ, Pospisilik JA. Developmental priming of cancer susceptibility. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.12.557446. [PMID: 37745326 PMCID: PMC10515831 DOI: 10.1101/2023.09.12.557446] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
DNA mutations are necessary drivers of cancer, yet only a small subset of mutated cells go on to cause the disease. To date, the mechanisms that determine which rare subset of cells transform and initiate tumorigenesis remain unclear. Here, we take advantage of a unique model of intrinsic developmental heterogeneity (Trim28+/D9) and demonstrate that stochastic early life epigenetic variation can trigger distinct cancer-susceptibility 'states' in adulthood. We show that these developmentally primed states are characterized by differential methylation patterns at typically silenced heterochromatin, and that these epigenetic signatures are detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential. These same genes are frequently mutated in human cancers, and their dysregulation correlates with poor prognosis. These results provide proof-of-concept that intrinsic developmental heterogeneity can prime individual, life-long cancer risk.
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Affiliation(s)
- Ilaria Panzeri
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
- Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Luca Fagnocchi
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - Stefanos Apostle
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - Megan Tompkins
- Vivarium and Transgenics Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Emily Wolfrum
- Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Zachary Madaj
- Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Galen Hostetter
- Pathology and Biorepository Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Yanqing Liu
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - Kristen Schaefer
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
- Department of Genetics and Genome Science, Case Western Reserve University, Cleveland, Ohio, USA
| | - Yang Chih-Hsiang
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
- Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
- Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA USA
| | - Alexis Bergsma
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
- Parkinson’s Disease Center, Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
| | - Anne Drougard
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - Erez Dror
- Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | | | - Darrell Chandler
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - Daniel Schramek
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Timothy J. Triche
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - J. Andrew Pospisilik
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
- Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
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26
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Tejedor JR, Peñarroya A, Gancedo-Verdejo J, Santamarina-Ojeda P, Pérez RF, López-Tamargo S, Díez-Borge A, Alba-Linares JJ, González-Del-Rey N, Urdinguio RG, Mangas C, Roberti A, López V, Morales-Ruiz T, Ariza RR, Roldán-Arjona T, Meijón M, Valledor L, Cañal MJ, Fernández-Martínez D, Fernández-Hevia M, Jiménez-Fonseca P, García-Flórez LJ, Fernández AF, Fraga MF. CRISPR/dCAS9-mediated DNA demethylation screen identifies functional epigenetic determinants of colorectal cancer. Clin Epigenetics 2023; 15:133. [PMID: 37612734 PMCID: PMC10464368 DOI: 10.1186/s13148-023-01546-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 08/03/2023] [Indexed: 08/25/2023] Open
Abstract
BACKGROUND Promoter hypermethylation of tumour suppressor genes is frequently observed during the malignant transformation of colorectal cancer (CRC). However, whether this epigenetic mechanism is functional in cancer or is a mere consequence of the carcinogenic process remains to be elucidated. RESULTS In this work, we performed an integrative multi-omic approach to identify gene candidates with strong correlations between DNA methylation and gene expression in human CRC samples and a set of 8 colon cancer cell lines. As a proof of concept, we combined recent CRISPR-Cas9 epigenome editing tools (dCas9-TET1, dCas9-TET-IM) with a customized arrayed gRNA library to modulate the DNA methylation status of 56 promoters previously linked with strong epigenetic repression in CRC, and we monitored the potential functional consequences of this DNA methylation loss by means of a high-content cell proliferation screen. Overall, the epigenetic modulation of most of these DNA methylated regions had a mild impact on the reactivation of gene expression and on the viability of cancer cells. Interestingly, we found that epigenetic reactivation of RSPO2 in the tumour context was associated with a significant impairment in cell proliferation in p53-/- cancer cell lines, and further validation with human samples demonstrated that the epigenetic silencing of RSPO2 is a mid-late event in the adenoma to carcinoma sequence. CONCLUSIONS These results highlight the potential role of DNA methylation as a driver mechanism of CRC and paves the way for the identification of novel therapeutic windows based on the epigenetic reactivation of certain tumour suppressor genes.
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Affiliation(s)
- Juan Ramón Tejedor
- Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), 33940, El Entrego, Asturias, Spain
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
- Spanish Biomedical Research Network in Rare Diseases (CIBERER), 28029, Madrid, Spain
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Asturias, Spain
| | - Alfonso Peñarroya
- Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), 33940, El Entrego, Asturias, Spain
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
| | - Javier Gancedo-Verdejo
- Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), 33940, El Entrego, Asturias, Spain
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
- Spanish Biomedical Research Network in Rare Diseases (CIBERER), 28029, Madrid, Spain
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Asturias, Spain
| | - Pablo Santamarina-Ojeda
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
- Spanish Biomedical Research Network in Rare Diseases (CIBERER), 28029, Madrid, Spain
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Asturias, Spain
| | - Raúl F Pérez
- Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), 33940, El Entrego, Asturias, Spain
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
- Spanish Biomedical Research Network in Rare Diseases (CIBERER), 28029, Madrid, Spain
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Asturias, Spain
| | - Sara López-Tamargo
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Asturias, Spain
| | - Ana Díez-Borge
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
- Viralgen Vector Core, 20009, San Sebastián, Gipuzkoa, Spain
| | - Juan J Alba-Linares
- Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), 33940, El Entrego, Asturias, Spain
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Asturias, Spain
| | - Nerea González-Del-Rey
- Department of Organisms and Systems Biology, Institute of Biotechnology of Asturias, University of Oviedo, 33071, Oviedo, Asturias, Spain
- Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain
| | - Rocío G Urdinguio
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
- Spanish Biomedical Research Network in Rare Diseases (CIBERER), 28029, Madrid, Spain
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Asturias, Spain
| | - Cristina Mangas
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Asturias, Spain
| | - Annalisa Roberti
- Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), 33940, El Entrego, Asturias, Spain
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
| | - Virginia López
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Asturias, Spain
| | - Teresa Morales-Ruiz
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14071, Córdoba, Spain
- Department of Genetics, University of Córdoba, 14071, Córdoba, Spain
| | - Rafael R Ariza
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14071, Córdoba, Spain
- Department of Genetics, University of Córdoba, 14071, Córdoba, Spain
| | - Teresa Roldán-Arjona
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14071, Córdoba, Spain
- Department of Genetics, University of Córdoba, 14071, Córdoba, Spain
| | - Mónica Meijón
- Department of Organisms and Systems Biology, Institute of Biotechnology of Asturias, University of Oviedo, 33071, Oviedo, Asturias, Spain
| | - Luis Valledor
- Department of Organisms and Systems Biology, Institute of Biotechnology of Asturias, University of Oviedo, 33071, Oviedo, Asturias, Spain
| | - María Jesús Cañal
- Department of Organisms and Systems Biology, Institute of Biotechnology of Asturias, University of Oviedo, 33071, Oviedo, Asturias, Spain
| | - Daniel Fernández-Martínez
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Asturias, Spain
- Division of General Surgery, Department of Colorectal Surgery, Central University Hospital of Asturias (HUCA), 33011, Oviedo, Asturias, Spain
| | - María Fernández-Hevia
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Asturias, Spain
- Division of General Surgery, Department of Colorectal Surgery, Central University Hospital of Asturias (HUCA), 33011, Oviedo, Asturias, Spain
| | - Paula Jiménez-Fonseca
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
- Division of Oncology, Department of Medical Oncology, Central University Hospital of Asturias (HUCA), 33011, Oviedo, Asturias, Spain
| | - Luis J García-Flórez
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Asturias, Spain
- Division of General Surgery, Department of Colorectal Surgery, Central University Hospital of Asturias (HUCA), 33011, Oviedo, Asturias, Spain
- Department of Surgery and Medical Surgical Specialties, University of Oviedo, 33006, Oviedo, Asturias, Spain
| | - Agustín F Fernández
- Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), 33940, El Entrego, Asturias, Spain.
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain.
- Spanish Biomedical Research Network in Rare Diseases (CIBERER), 28029, Madrid, Spain.
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Asturias, Spain.
| | - Mario F Fraga
- Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), 33940, El Entrego, Asturias, Spain.
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011, Oviedo, Asturias, Spain.
- Spanish Biomedical Research Network in Rare Diseases (CIBERER), 28029, Madrid, Spain.
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Asturias, Spain.
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27
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Cui W, Huang Z, Jin SG, Johnson J, Lau KH, Hostetter G, Pfeifer GP. Deficiency of the Polycomb Protein RYBP and TET Methylcytosine Oxidases Promotes Extensive CpG Island Hypermethylation and Malignant Transformation. Cancer Res 2023; 83:2480-2495. [PMID: 37272752 PMCID: PMC10391329 DOI: 10.1158/0008-5472.can-23-0269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 04/24/2023] [Accepted: 05/31/2023] [Indexed: 06/06/2023]
Abstract
Hypermethylation of CpG islands (CGI) is a common feature of cancer cells and predominantly affects Polycomb-associated genomic regions. Elucidating the underlying mechanisms leading to DNA hypermethylation in human cancer could help identify chemoprevention strategies. Here, we evaluated the role of Polycomb complexes and 5-methylcytosine (5mC) oxidases in protecting CGIs from DNA methylation and observed that four genes coding for components of Polycomb repressive complex 1 (PRC1) are downregulated in tumors. Inactivation of RYBP, a key activator of variant PRC1 complexes, in combination with all three 5mC oxidases (TET proteins) in nontumorigenic bronchial epithelial cells led to widespread hypermethylation of Polycomb-marked CGIs affecting almost 4,000 target genes, which closely resembled the DNA hypermethylation landscape observed in human squamous cell lung tumors. The RYBP- and TET-deficient cells showed methylation-associated aberrant regulation of cancer-relevant pathways, including defects in the Hippo tumor suppressor network. Notably, the quadruple knockout cells acquired a transformed phenotype, including anchorage-independent growth and formation of squamous cell carcinomas in mice. This work provides a mechanism promoting hypermethylation of CGIs and shows that such hypermethylation can lead to cell transformation. The breakdown of a two-pronged protection mechanism can be a route towards genome-wide hypermethylation of CGIs in tumors. SIGNIFICANCE Dysfunction of the Polycomb component RYBP in combination with loss of 5-methylcytosine oxidases promotes widespread hypermethylation of CpG islands in bronchial cells and induces tumorigenesis, resembling changes seen in human lung tumors.
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Affiliation(s)
- Wei Cui
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan
| | - Zhijun Huang
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan
| | - Seung-Gi Jin
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan
| | - Jennifer Johnson
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan
| | - Kin H. Lau
- Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, Michigan
| | - Galen Hostetter
- Pathology and Biorepository Core, Van Andel Institute, Grand Rapids, Michigan
| | - Gerd P. Pfeifer
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan
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28
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Bhandari YR, Krishna V, Powers R, Parmar S, Thursby SJ, Gupta E, Kulak O, Gokare P, Reumers J, Van Wesenbeeck L, Bachman KE, Baylin SB, Easwaran H. Transcription factor expression repertoire basis for epigenetic and transcriptional subtypes of colorectal cancers. Proc Natl Acad Sci U S A 2023; 120:e2301536120. [PMID: 37487069 PMCID: PMC10401032 DOI: 10.1073/pnas.2301536120] [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: 02/03/2023] [Accepted: 06/15/2023] [Indexed: 07/26/2023] Open
Abstract
Colorectal cancers (CRCs) form a heterogenous group classified into epigenetic and transcriptional subtypes. The basis for the epigenetic subtypes, exemplified by varying degrees of promoter DNA hypermethylation, and its relation to the transcriptional subtypes is not well understood. We link cancer-specific transcription factor (TF) expression alterations to methylation alterations near TF-binding sites at promoter and enhancer regions in CRCs and their premalignant precursor lesions to provide mechanistic insights into the origins and evolution of the CRC molecular subtypes. A gradient of TF expression changes forms a basis for the subtypes of abnormal DNA methylation, termed CpG-island promoter DNA methylation phenotypes (CIMPs), in CRCs and other cancers. CIMP is tightly correlated with cancer-specific hypermethylation at enhancers, which we term CpG-enhancer methylation phenotype (CEMP). Coordinated promoter and enhancer methylation appears to be driven by downregulation of TFs with common binding sites at the hypermethylated enhancers and promoters. The altered expression of TFs related to hypermethylator subtypes occurs early during CRC development, detectable in premalignant adenomas. TF-based profiling further identifies patients with worse overall survival. Importantly, altered expression of these TFs discriminates the transcriptome-based consensus molecular subtypes (CMS), thus providing a common basis for CIMP and CMS subtypes.
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Affiliation(s)
- Yuba R. Bhandari
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD21287
| | - Vinod Krishna
- Infectious Diseases and Vaccines Therapeutic Area, Janssen Research and Development, Spring House, PA19477
| | - Rachael Powers
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD21287
| | - Sehej Parmar
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD21287
| | - Sara-Jayne Thursby
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD21287
| | - Ekta Gupta
- Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, MD21287
| | - Ozlem Kulak
- Division of Gastrointestinal and Liver Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD21287
| | - Prashanth Gokare
- Oncology Therapeutic Area, Janssen Research and Development, Spring House, PA19477
| | - Joke Reumers
- Discovery Technologies and Molecular Pharmacology, Therapeutics Discovery, Janssen Research and Development, Turnhoutseweg 30, 2340Beerse, Belgiumg
| | - Liesbeth Van Wesenbeeck
- Infectious Diseases and Vaccines Therapeutic Area, Janssen Research and Development, Turnhoutseweg 30, 2340Beerse, Belgium
| | - Kurtis E. Bachman
- Oncology Therapeutic Area, Janssen Research and Development, Spring House, PA19477
| | - Stephen B. Baylin
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD21287
| | - Hariharan Easwaran
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD21287
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29
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Mohan DR, Borges KS, Finco I, LaPensee CR, Rege J, Solon AL, Little DW, Else T, Almeida MQ, Dang D, Haggerty-Skeans J, Apfelbaum AA, Vinco M, Wakamatsu A, Mariani BMP, Amorim LC, Latronico AC, Mendonca BB, Zerbini MCN, Lawlor ER, Ohi R, Auchus RJ, Rainey WE, Marie SKN, Giordano TJ, Venneti S, Fragoso MCBV, Breault DT, Lerario AM, Hammer GD. β-Catenin-Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer. Cancer Res 2023; 83:2123-2141. [PMID: 37129912 PMCID: PMC10330305 DOI: 10.1158/0008-5472.can-22-2712] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 03/19/2023] [Accepted: 04/28/2023] [Indexed: 05/03/2023]
Abstract
Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent β-catenin-activating mutations. Here, we demonstrated that ACC differentiation is maintained by a balance between nuclear, tissue-specific β-catenin-containing complexes, and the epigenome. On chromatin, β-catenin bound master adrenal transcription factor SF1 and hijacked the adrenocortical super-enhancer landscape to maintain differentiation in CIMP-high ACC; off chromatin, β-catenin bound histone methyltransferase EZH2. SF1/β-catenin and EZH2/β-catenin complexes present in normal adrenals persisted through all phases of ACC evolution. Pharmacologic EZH2 inhibition in CIMP-high ACC expelled SF1/β-catenin from chromatin and favored EZH2/β-catenin assembly, erasing differentiation and restraining cancer growth in vitro and in vivo. These studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities. SIGNIFICANCE Oncogenic β-catenin can use tissue-specific partners to regulate cellular differentiation programs that can be reversed by epigenetic therapies, identifying epigenetic control of differentiation as a viable target for β-catenin-driven cancers.
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Affiliation(s)
- Dipika R. Mohan
- Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA
- Doctoral Program in Cancer Biology, University of Michigan, Ann Arbor, MI, USA
| | - Kleiton S. Borges
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Isabella Finco
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Christopher R. LaPensee
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Juilee Rege
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - April L. Solon
- Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Donald W. Little
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Tobias Else
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Madson Q. Almeida
- Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Departamento de Clínica Médica, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, SP, Brazil
- Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, SP, Brazil
| | - Derek Dang
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Laboratory of Brain Tumor Metabolism and Epigenetics, University of Michigan, Ann Arbor, MI, USA
| | - James Haggerty-Skeans
- Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Laboratory of Brain Tumor Metabolism and Epigenetics, University of Michigan, Ann Arbor, MI, USA
| | - April A. Apfelbaum
- Doctoral Program in Cancer Biology, University of Michigan, Ann Arbor, MI, USA
- Seattle Children’s Research Institute, University of Washington, Seattle, WA, USA
| | - Michelle Vinco
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Alda Wakamatsu
- Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, SP, Brazil
| | - Beatriz M. P. Mariani
- Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Departamento de Clínica Médica, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, SP, Brazil
| | - Larissa Costa Amorim
- Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Departamento de Clínica Médica, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, SP, Brazil
- Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, SP, Brazil
| | - Ana Claudia Latronico
- Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Departamento de Clínica Médica, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, SP, Brazil
| | - Berenice B. Mendonca
- Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Departamento de Clínica Médica, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, SP, Brazil
| | | | - Elizabeth R. Lawlor
- Seattle Children’s Research Institute, University of Washington, Seattle, WA, USA
- Department of Pediatrics, University of Washington, Seattle, WA, USA
| | - Ryoma Ohi
- Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Richard J. Auchus
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
- Lieutenant Colonel Charles S. Kettles Veterans Affairs Medical Center, Ann Arbor, MI, USA
- Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA
| | - William E. Rainey
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Suely K. N. Marie
- Laboratório de Biologia Molecular e Celular/LIM15, Departamento de Neurologia, Faculdade de Medicina da Universidade de São Paulo, SP, Brazil
| | - Thomas J. Giordano
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center Endocrine Oncology Program, University of Michigan, Ann Arbor, MI, USA
| | - Sriram Venneti
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Laboratory of Brain Tumor Metabolism and Epigenetics, University of Michigan, Ann Arbor, MI, USA
- Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA
| | - Maria Candida Barisson Villares Fragoso
- Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Departamento de Clínica Médica, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, SP, Brazil
- Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, SP, Brazil
| | - David T. Breault
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
- Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA
| | - Antonio Marcondes Lerario
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
- Co-senior authors
| | - Gary D. Hammer
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
- Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center Endocrine Oncology Program, University of Michigan, Ann Arbor, MI, USA
- Co-senior authors
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30
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Lu Y, Cao Q, Yu Y, Sun Y, Jiang X, Li X. Pan-cancer analysis revealed H3K4me1 at bivalent promoters premarks DNA hypermethylation during tumor development and identified the regulatory role of DNA methylation in relation to histone modifications. BMC Genomics 2023; 24:235. [PMID: 37138231 PMCID: PMC10157937 DOI: 10.1186/s12864-023-09341-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 04/27/2023] [Indexed: 05/05/2023] Open
Abstract
BACKGROUND DNA hypermethylation at promoter CpG islands (CGIs) is a hallmark of cancers and could lead to dysregulation of gene expression in the development of cancers, however, its dynamics and regulatory mechanisms remain elusive. Bivalent genes, that direct development and differentiation of stem cells, are found to be frequent targets of hypermethylation in cancers. RESULTS Here we performed comprehensive analysis across multiple cancer types and identified that the decrease in H3K4me1 levels coincides with DNA hypermethylation at the bivalent promoter CGIs during tumorigenesis. Removal of DNA hypermethylation leads to increment of H3K4me1 at promoter CGIs with preference for bivalent genes. Nevertheless, the alteration of H3K4me1 by overexpressing or knockout LSD1, the demethylase of H3K4, doesn't change the level or pattern of DNA methylation. Moreover, LSD1 was found to regulate the expression of a bivalent gene OVOL2 to promote tumorigenesis. Knockdown of OVOL2 in LSD1 knockout HCT116 cells restored the cancer cell phenotype. CONCLUSION In summary, our work identified a universal indicator that can pre-mark DNA hypermethylation in cancer cells, and dissected the interplay between H3K4me1 and DNA hypermethylation in detail. Current study also reveals a novel mechanism underlying the oncogenic role of LSD1, providing clues for cancer therapies.
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Affiliation(s)
- Yang Lu
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China
| | - Qiang Cao
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China
| | - Yue Yu
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China
| | - Yazhou Sun
- The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Xuan Jiang
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China.
| | - Xin Li
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China.
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31
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Barrett JE, Jones A, Evans I, Herzog C, Reisel D, Olaitan A, Mould T, MacDonald N, Doufekas K, Newton C, Crosbie EJ, Bjørge L, Colombo N, Dostalek L, Costas L, Peremiquel-Trillas P, Ponce J, Matias-Guiu X, Zikan M, Cibula D, Wang J, Sundström K, Dillner J, Widschwendter M. The WID-EC test for the detection and risk prediction of endometrial cancer. Int J Cancer 2023; 152:1977-1988. [PMID: 36533702 DOI: 10.1002/ijc.34406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 11/15/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022]
Abstract
The incidence of endometrial cancer is rising. Measures to identify women at risk and to detect endometrial cancer earlier are required to reduce the morbidity triggered by the aggressive treatment required for advanced endometrial cancer. We developed the WID-EC (Women's cancer risk IDentification-Endometrial Cancer) test, which is based on DNA methylation at 500 CpG sites, in a discovery set of cervical liquid-based cytology samples from 1086 women with and without an endometrial cancer (217 cancer cases and 869 healthy controls) with a worse prognosis (grade 3 or ≥stage IB). We validated the WID-EC test in an independent external validation set of 64 endometrial cancer cases and 225 controls. We further validated the test in 150 healthy women (prospective set) who provided a cervical sample as part of the routine Swedish cervical screening programme, 54 of whom developed endometrial cancer within 3 years of sample collection. The WID-EC test identified women with endometrial cancer with a receiver operator characteristic area under the curve (AUC) of 0.92 (95% CI: 0.88-0.97) in the external set and of 0.82 (95% CI: 0.74-0.89) in the prospective validation set. Using an optimal cutoff, cancer cases were detected with a sensitivity of 86% and a specificity of 90% in the external validation set, and a sensitivity and specificity of 52% and 98% respectively in the prospective validation set. The WID-EC test can identify women with or at risk of endometrial cancer.
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Affiliation(s)
- James E Barrett
- European Translational Oncology Prevention and Screening (EUTOPS) Institute, Hall in Tirol, Austria.,Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, London, UK.,Research Institute for Biomedical Aging Research, Universität Innsbruck, Innsbruck, Austria
| | - Allison Jones
- Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, London, UK
| | - Iona Evans
- Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, London, UK
| | - Chiara Herzog
- European Translational Oncology Prevention and Screening (EUTOPS) Institute, Hall in Tirol, Austria
| | - Daniel Reisel
- Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, London, UK
| | - Adeola Olaitan
- Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, London, UK
| | - Tim Mould
- Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, London, UK
| | - Nicola MacDonald
- Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, London, UK
| | - Konstantinos Doufekas
- Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, London, UK
| | - Claire Newton
- University Hospitals Bristol NHS Foundation Trust, Bristol, UK.,University of Bristol, Bristol, UK
| | - Emma J Crosbie
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.,Division of Gynaecology, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Line Bjørge
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.,Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Nicoletta Colombo
- Istituto Europeo di Oncologia, Milan, Italy.,University of Milano-Bicocca, Milan, Italy
| | - Lukas Dostalek
- Hospital Na Bulovce, Prague, Czech Republic.,Department of Obstetrics and Gynecology, General University Hospital in Prague, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Laura Costas
- Unit of Molecular Epidemiology and Genetics in Infections and Cancer, Cancer Epidemiology Research Programme, IDIBELL, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Paula Peremiquel-Trillas
- Unit of Molecular Epidemiology and Genetics in Infections and Cancer, Cancer Epidemiology Research Programme, IDIBELL, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Jordi Ponce
- Department of Gynecology and Obstetrics, Hospital Universitari de Bellvitge, IDIBELL. Hospitalet de Llobregat, Barcelona, Spain
| | - Xavier Matias-Guiu
- Department of Pathology, Hospital Universitari de Bellvitge, IDIBELL, CIBERONC. Hospitalet de Llobregat, Barcelona, Spain
| | - Michal Zikan
- Hospital Na Bulovce, Prague, Czech Republic.,Department of Obstetrics and Gynecology, General University Hospital in Prague, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - David Cibula
- Department of Obstetrics and Gynecology, General University Hospital in Prague, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jiangrong Wang
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Karin Sundström
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Joakim Dillner
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Martin Widschwendter
- European Translational Oncology Prevention and Screening (EUTOPS) Institute, Hall in Tirol, Austria.,Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, London, UK.,Research Institute for Biomedical Aging Research, Universität Innsbruck, Innsbruck, Austria
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32
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Yu Y, Li X, Jiao R, Lu Y, Jiang X, Li X. H3K27me3-H3K4me1 transition at bivalent promoters instructs lineage specification in development. Cell Biosci 2023; 13:66. [PMID: 36991495 DOI: 10.1186/s13578-023-01017-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 03/20/2023] [Indexed: 03/31/2023] Open
Abstract
BACKGROUND Bivalent genes, of which promoters are marked by both H3K4me3 (trimethylation of histone H3 on lysine 4) and H3K27me3 (trimethylation of histone H3 on lysine 27), play critical roles in development and tumorigenesis. Monomethylation on lysine 4 of histone H3 (H3K4me1) is commonly associated with enhancers, but H3K4me1 is also present at promoter regions as an active bimodal or a repressed unimodal pattern. Whether the co-occurrence of H3K4me1 and bivalent marks at promoters plays regulatory role in development is largely unknown. RESULTS We report that in the process of lineage differentiation, bivalent promoters undergo H3K27me3-H3K4me1 transition, the loss of H3K27me3 accompanies by bimodal pattern loss or unimodal pattern enrichment of H3K4me1. More importantly, this transition regulates tissue-specific gene expression to orchestrate the development. Furthermore, knockout of Eed (Embryonic Ectoderm Development) or Suz12 (Suppressor of Zeste 12) in mESCs (mouse embryonic stem cells), the core components of Polycomb repressive complex 2 (PRC2) which catalyzes H3K27 trimethylation, generates an artificial H3K27me3-H3K4me1 transition at partial bivalent promoters, which leads to up-regulation of meso-endoderm related genes and down-regulation of ectoderm related genes, thus could explain the observed neural ectoderm differentiation failure upon retinoic acid (RA) induction. Finally, we find that lysine-specific demethylase 1 (LSD1) interacts with PRC2 and contributes to the H3K27me3-H3K4me1 transition in mESCs. CONCLUSIONS These findings suggest that H3K27me3-H3K4me1 transition plays a key role in lineage differentiation by regulating the expression of tissue specific genes, and H3K4me1 pattern in bivalent promoters could be modulated by LSD1 via interacting with PRC2.
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Affiliation(s)
- Yue Yu
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Xinjie Li
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Rui Jiao
- The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Yang Lu
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Xuan Jiang
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, China.
| | - Xin Li
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
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33
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Kondo S, Okabe A, Nakagawa T, Matsusaka K, Fukuyo M, Rahmutulla B, Dochi H, Mizokami H, Kitagawa Y, Kurokawa T, Mima M, Endo K, Sugimoto H, Wakisaka N, Misawa K, Yoshizaki T, Kaneda A. Repression of DERL3 via DNA methylation by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166598. [PMID: 36372158 DOI: 10.1016/j.bbadis.2022.166598] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 08/05/2022] [Accepted: 10/22/2022] [Indexed: 11/13/2022]
Abstract
Nasopharyngeal carcinoma (NPC) is Epstein-Barr virus (EBV)-associated invasive malignancy. Increasing evidence indicates that epigenetic abnormalities, including DNA methylation, play important roles in the development of NPC. In particular, the EBV principal oncogene, latent membrane protein 1 (LMP1), is considered a key factor in inducing aberrant DNA methylation of several tumour suppressor genes in NPC, although the mechanism remains unclear. Herein, we comprehensively analysed the methylome data of Infinium BeadArray from 51 NPC and 52 normal nasopharyngeal tissues to identify LMP1-inducible methylation genes. Using hierarchical clustering analysis, we classified NPC into the high-methylation, low-methylation, and normal-like subgroups. We defined high-methylation genes as those that were methylated in the high-methylation subgroup only and common methylation genes as those that were methylated in both high- and low-methylation subgroups. Subsequently, we identified 715 LMP1-inducible methylation genes by observing the methylome data of the nasopharyngeal epithelial cell line with or without LMP1 expression. Because high-methylation genes were enriched with LMP1-inducible methylation genes, we extracted 95 high-methylation genes that overlapped with the LMP1-inducible methylation genes. Among them, we identified DERL3 as the most significantly methylated gene affected by LMP1 expression. DERL3 knockdown in cell lines resulted in significantly increased cell proliferation, migration, and invasion. Lower DERL3 expression was more frequently detected in the advanced T-stage NPC than in early T-stage NPC. These results indicate that DERL3 repression by DNA methylation contributes to NPC tumour progression.
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Affiliation(s)
- Satoru Kondo
- Division of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan; Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-0856, Japan
| | - Atsushi Okabe
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-0856, Japan
| | - Takuya Nakagawa
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-0856, Japan; Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-2856, Japan
| | - Keisuke Matsusaka
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-0856, Japan; Department of Pathology, Chiba University Hospital, Chiba, Chiba 260-2856, Japan
| | - Masaki Fukuyo
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-0856, Japan; Department of Genome Research and Development, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan
| | - Bahityar Rahmutulla
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-0856, Japan
| | - Hirotomo Dochi
- Division of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan
| | - Harue Mizokami
- Division of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan; Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-0856, Japan
| | - Yuki Kitagawa
- Division of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan
| | - Tomoya Kurokawa
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-0856, Japan; Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-2856, Japan
| | - Masato Mima
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-0856, Japan; Department of Otorhinolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Kazuhira Endo
- Division of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan
| | - Hisashi Sugimoto
- Division of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan
| | - Naohiro Wakisaka
- Division of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan
| | - Kiyoshi Misawa
- Department of Otorhinolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Tomokazu Yoshizaki
- Division of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan
| | - Atsushi Kaneda
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-0856, Japan.
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Ding W, Kaur D, Horvath S, Zhou W. Comparative epigenome analysis using Infinium DNA methylation BeadChips. Brief Bioinform 2023; 24:6974838. [PMID: 36617464 PMCID: PMC10147478 DOI: 10.1093/bib/bbac617] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/05/2022] [Accepted: 12/15/2022] [Indexed: 01/10/2023] Open
Abstract
The arrival of the Infinium DNA methylation BeadChips for mice and other nonhuman mammalian species has outpaced the development of the informatics that supports their use for epigenetics study in model organisms. Here, we present informatics infrastructure and methods to allow easy DNA methylation analysis on multiple species, including domesticated animals and inbred laboratory mice (in SeSAMe version 1.16.0+). First, we developed a data-driven analysis pipeline covering species inference, genome-specific data preprocessing and regression modeling. We targeted genomes of 310 species and 37 inbred mouse strains and showed that genome-specific preprocessing prevents artifacts and yields more accurate measurements than generic pipelines. Second, we uncovered the dynamics of the epigenome evolution in different genomic territories and tissue types through comparative analysis. We identified a catalog of inbred mouse strain-specific methylation differences, some of which are linked to the strains' immune, metabolic and neurological phenotypes. By streamlining DNA methylation array analysis for undesigned genomes, our methods extend epigenome research to broad species contexts.
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Affiliation(s)
- Wubin Ding
- Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, PA, 19104, USA
| | - Diljeet Kaur
- Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, PA, 19104, USA
| | - Steve Horvath
- Dept. of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.,Altos Labs, San Diego, CA, USA
| | - Wanding Zhou
- Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, PA, 19104, USA.,Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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Abstract
Mutations in epigenetic regulators are prevalent in cancer, but their functional impact is poorly delineated aside from disrupting differentiation. In this issue of Cancer Cell, Loukas et al. zoom in on the late occurring, subclonal subset of such mutations and define the molecular mechanism behind their enrichment in cancer.
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Affiliation(s)
- Hui Shen
- Department of Epigenetics, Van Andel Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503, USA.
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36
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Bhootra S, Jill N, Shanmugam G, Rakshit S, Sarkar K. DNA methylation and cancer: transcriptional regulation, prognostic, and therapeutic perspective. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2023; 40:71. [PMID: 36602616 DOI: 10.1007/s12032-022-01943-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 12/25/2022] [Indexed: 01/06/2023]
Abstract
DNA methylation is one among the major grounds of cancer progression which is characterized by the addition of a methyl group to the promoter region of the gene thereby causing gene silencing or increasing the probability of mutations; however, in bacteria, methylation is used as a defense mechanism where DNA protection is by addition of methyl groups making restriction enzymes unable to cleave. Hypermethylation and hypomethylation both pose as leading causes of oncogenesis; the former being more frequent which occurs at the CpG islands present in the promoter region of the genes, whereas the latter occurs globally in various genomic sequences. Reviewing methylation profiles would help in the detection and treatment of cancers. Demethylation is defined as preventing methyl group addition to the cytosine DNA base which could cause cancers in case of global hypomethylation, however, upon further investigation; it could be used as a therapeutic tool as well as for drug design in cancer treatment. In this review, we have studied the molecules that induce and enzymes (DNMTs) that bring about methylation as well as comprehend the correlation between methylation with transcription factors and various signaling pathways. DNA methylation has also been reviewed in terms of how it could serve as a prognostic marker and the various therapeutic drugs that have come into the market for reversing methylation opening an avenue toward curing cancers.
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Affiliation(s)
- Sannidhi Bhootra
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Nandana Jill
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Geetha Shanmugam
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Sudeshna Rakshit
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Koustav Sarkar
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India.
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Aminzadeh-Gohari S, Kofler B, Herzog C. Dietary restriction in senolysis and prevention and treatment of disease. Crit Rev Food Sci Nutr 2022; 64:5242-5268. [PMID: 36484738 PMCID: PMC7616065 DOI: 10.1080/10408398.2022.2153355] [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] [Indexed: 12/13/2022]
Abstract
Aging represents a key risk factor for a plethora of diseases. Targeting detrimental processes which occur during aging, especially before onset of age-related disease, could provide drastic improvements in healthspan. There is increasing evidence that dietary restriction (DR), including caloric restriction, fasting, or fasting-mimicking diets, extend both lifespan and healthspan. This has sparked interest in the use of dietary regimens as a non-pharmacological means to slow aging and prevent disease. Here, we review the current evidence on the molecular mechanisms underlying DR-induced health improvements, including removal of senescent cells, metabolic reprogramming, and epigenetic rejuvenation.
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Affiliation(s)
- Sepideh Aminzadeh-Gohari
- Research Program for Receptor Biochemistry and Tumor Metabollism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
- European Translational Oncology Prevention and Screening Institute, Universität Innsbruck, Innsbruck, Austria
- Research Institute for Biomedical Ageing, Universität Innsbruck, Innsbruck, Austria
| | - Barbara Kofler
- Research Program for Receptor Biochemistry and Tumor Metabollism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
| | - Chiara Herzog
- European Translational Oncology Prevention and Screening Institute, Universität Innsbruck, Innsbruck, Austria
- Research Institute for Biomedical Ageing, Universität Innsbruck, Innsbruck, Austria
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38
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Castaneda M, den Hollander P, Kuburich NA, Rosen JM, Mani SA. Mechanisms of cancer metastasis. Semin Cancer Biol 2022; 87:17-31. [PMID: 36354098 DOI: 10.1016/j.semcancer.2022.10.006] [Citation(s) in RCA: 93] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 10/10/2022] [Accepted: 10/25/2022] [Indexed: 11/09/2022]
Abstract
Metastatic cancer is almost always terminal, and more than 90% of cancer deaths result from metastatic disease. Combating cancer metastasis and post-therapeutic recurrence successfully requires understanding each step of metastatic progression. This review describes the current state of knowledge of the etiology and mechanism of cancer progression from primary tumor growth to the formation of new tumors in other parts of the body. Open questions, avenues for future research, and therapeutic approaches with the potential to prevent or inhibit metastasis through personalization to each patient's mutation and/or immune profile are also highlighted.
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Affiliation(s)
- Maria Castaneda
- Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Petra den Hollander
- Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology and Lab Medicine, Brown University, Providence, RI 02912, USA; Legoretta Cancer Center, Brown University, Providence, RI 021912, USA
| | - Nick A Kuburich
- Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology and Lab Medicine, Brown University, Providence, RI 02912, USA; Legoretta Cancer Center, Brown University, Providence, RI 021912, USA
| | - Jeffrey M Rosen
- Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Sendurai A Mani
- Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology and Lab Medicine, Brown University, Providence, RI 02912, USA; Legoretta Cancer Center, Brown University, Providence, RI 021912, USA.
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Pérez RF, Tejedor JR, Fernández AF, Fraga MF. Aging and cancer epigenetics: Where do the paths fork? Aging Cell 2022; 21:e13709. [PMID: 36103298 PMCID: PMC9577950 DOI: 10.1111/acel.13709] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 08/29/2022] [Indexed: 01/25/2023] Open
Abstract
Aging and cancer are clearly associated processes, at both the epidemiological and molecular level. Epigenetic mechanisms are good candidates to explain the molecular links between the two phenomena, but recent reports have also revealed considerable differences, particularly regarding the loss of DNA methylation in the two processes. The large-scale generation and availability of genome-wide epigenetic data now permits systematic studies to be undertaken which may help clarify the similarities and differences between aging and cancer epigenetic alterations. In addition, the development of epigenetic clocks provides a new dimension in which to investigate diseases at the molecular level. Here, we examine current and future questions about the roles of DNA methylation mechanisms as causal factors in the processes of aging and cancer so that we may better understand if and how aging-associated epigenetic alterations lead to tumorigenesis. It seems certain that comprehending the molecular mechanisms underlying epigenetic clocks, especially with regard to somatic stem cell aging, combined with applying single-cell epigenetic-age profiling technologies to aging and cancer cohorts, and the integration of existing and upcoming epigenetic evidence within the genetic damage models of aging will prove to be crucial to improving understanding of these two interrelated phenomena.
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Affiliation(s)
- Raúl Fernández Pérez
- Cancer Epigenetics and Nanomedicine LaboratoryNanomaterials and Nanotechnology Research Center (CINN‐CSIC)El EntregoSpain
- Health Research Institute of Asturias (ISPA‐FINBA)Institute of Oncology of Asturias (IUOPA) and Department of Organisms and Systems Biology (BOS)University of OviedoOviedoSpain
- Rare Diseases CIBER (CIBERER)Carlos III Health Institute (ISCIII)MadridSpain
| | - Juan Ramón Tejedor
- Cancer Epigenetics and Nanomedicine LaboratoryNanomaterials and Nanotechnology Research Center (CINN‐CSIC)El EntregoSpain
- Health Research Institute of Asturias (ISPA‐FINBA)Institute of Oncology of Asturias (IUOPA) and Department of Organisms and Systems Biology (BOS)University of OviedoOviedoSpain
- Rare Diseases CIBER (CIBERER)Carlos III Health Institute (ISCIII)MadridSpain
| | - Agustín Fernández Fernández
- Cancer Epigenetics and Nanomedicine LaboratoryNanomaterials and Nanotechnology Research Center (CINN‐CSIC)El EntregoSpain
- Health Research Institute of Asturias (ISPA‐FINBA)Institute of Oncology of Asturias (IUOPA) and Department of Organisms and Systems Biology (BOS)University of OviedoOviedoSpain
- Rare Diseases CIBER (CIBERER)Carlos III Health Institute (ISCIII)MadridSpain
| | - Mario Fernández Fraga
- Cancer Epigenetics and Nanomedicine LaboratoryNanomaterials and Nanotechnology Research Center (CINN‐CSIC)El EntregoSpain
- Health Research Institute of Asturias (ISPA‐FINBA)Institute of Oncology of Asturias (IUOPA) and Department of Organisms and Systems Biology (BOS)University of OviedoOviedoSpain
- Rare Diseases CIBER (CIBERER)Carlos III Health Institute (ISCIII)MadridSpain
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40
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Staaf J, Aine M. Tumor purity adjusted beta values improve biological interpretability of high-dimensional DNA methylation data. PLoS One 2022; 17:e0265557. [PMID: 36084090 PMCID: PMC9462735 DOI: 10.1371/journal.pone.0265557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 08/15/2022] [Indexed: 11/19/2022] Open
Abstract
A common issue affecting DNA methylation analysis in tumor tissue is the presence of a substantial amount of non-tumor methylation signal derived from the surrounding microenvironment. Although approaches for quantifying and correcting for the infiltration component have been proposed previously, we believe these have not fully addressed the issue in a comprehensive and universally applicable way. We present a multi-population framework for adjusting DNA methylation beta values on the Illumina 450/850K platform using generic purity estimates to account for non-tumor signal. Our approach also provides an indirect estimate of the aggregate methylation state of the surrounding normal tissue. Using whole exome sequencing derived purity estimates and Illumina 450K methylation array data generated by The Cancer Genome Atlas project (TCGA), we provide a demonstration of this framework in breast cancer illustrating the effect of beta correction on the aggregate methylation beta value distribution, clustering accuracy, and global methylation profiles.
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Affiliation(s)
- Johan Staaf
- Department of Clinical Sciences Lund, Division of Oncology, Lund University, Medicon Village, Lund, Sweden
| | - Mattias Aine
- Department of Clinical Sciences Lund, Division of Oncology, Lund University, Medicon Village, Lund, Sweden
- * E-mail:
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41
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Alimohammadi M, Makaremi S, Rahimi A, Asghariazar V, Taghadosi M, Safarzadeh E. DNA methylation changes and inflammaging in aging-associated diseases. Epigenomics 2022; 14:965-986. [PMID: 36043685 DOI: 10.2217/epi-2022-0143] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aging as an inevitable phenomenon is associated with pervasive changes in physiological functions. There is a relationship between aging and the increase of several chronic diseases. Most age-related disorders are accompanied by an underlying chronic inflammatory state, as demonstrated by local infiltration of inflammatory cells and greater levels of proinflammatory cytokines in the bloodstream. Within inflammaging, many epigenetic events, especially DNA methylation, change. During the aging process, due to aberrations of DNA methylation, biological processes are disrupted, leading to the emergence or progression of a variety of human diseases, including cancer, neurodegenerative disorders, cardiovascular disease and diabetes. The focus of this review is on DNA methylation, which is involved in inflammaging-related activities, and how its dysregulation leads to human disorders.
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Affiliation(s)
- Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1983969411, Iran
| | - Shima Makaremi
- School of Medicine & Allied Medical Sciences, Ardabil University of Medical Sciences, Ardabil, 5618985991, Iran
| | - Ali Rahimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, 5618985991, Iran
| | - Vahid Asghariazar
- Deputy of Research & Technology, Ardabil University of Medical Sciences, Ardabil, 5618985991, Iran
| | - Mahdi Taghadosi
- Department of Immunology, Kermanshah University of Medical Sciences, Kermanshah, 6714869914, Iran
| | - Elham Safarzadeh
- Department of Microbiology, Parasitology, & Immunology, Ardabil University of Medical Sciences, Ardabil, 5618985991, Iran
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42
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Xiao C, Wu G, Chen P, Gao L, Chen G, Zhang H. Phase separation in epigenetics and cancer stem cells. Front Oncol 2022; 12:922604. [PMID: 36081552 PMCID: PMC9445202 DOI: 10.3389/fonc.2022.922604] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 07/25/2022] [Indexed: 12/12/2022] Open
Abstract
Accumulating evidence indicates that liquid–liquid phase separation (LLPS) is the basis of the formation of membrane-less compartments in cells. This biomolecular condensate represented by phase separation may influence epigenetics in cancer stem cells (CSCs), a small subpopulation of cancer cells responding to the initiation, maintenance, metastasis, and therapy resistance of cancer. Understanding the underlying biophysical principles and the specific characteristics of biocondensates would provide insights into the precise blocking of potential tumor targets, thereby fundamentally curbing tumor occurrence, recurrence and metastasis. In this review, we summarized the key phenomenon and experimental detection of phase separation and the possibility of regulating the stemness of CSCs through phase separation. We believe that the mechanism of phase separation in CSCs will open up new avenues for the mystery of tumor formation, and modulating phase separation will be a great strategy for CSC-targeted tumor therapy.
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Affiliation(s)
- Chanchan Xiao
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, China
- Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China
- Guangdong-Hongkong-Macao Great Bay Area Geroscience Joint Laboratory (GBGJL), School of Medicine, Jinan University, Guangzhou, China
| | - Guangjie Wu
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, China
- Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China
- Guangdong-Hongkong-Macao Great Bay Area Geroscience Joint Laboratory (GBGJL), School of Medicine, Jinan University, Guangzhou, China
| | - Pengfei Chen
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, China
- Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China
- Guangdong-Hongkong-Macao Great Bay Area Geroscience Joint Laboratory (GBGJL), School of Medicine, Jinan University, Guangzhou, China
| | - Lijuan Gao
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, China
- Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China
- Guangdong-Hongkong-Macao Great Bay Area Geroscience Joint Laboratory (GBGJL), School of Medicine, Jinan University, Guangzhou, China
- *Correspondence: Lijuan Gao, ; Guobing Chen, ; Hongyi Zhang,
| | - Guobing Chen
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, China
- Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China
- Guangdong-Hongkong-Macao Great Bay Area Geroscience Joint Laboratory (GBGJL), School of Medicine, Jinan University, Guangzhou, China
- *Correspondence: Lijuan Gao, ; Guobing Chen, ; Hongyi Zhang,
| | - Hongyi Zhang
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, China
- Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China
- Guangdong-Hongkong-Macao Great Bay Area Geroscience Joint Laboratory (GBGJL), School of Medicine, Jinan University, Guangzhou, China
- *Correspondence: Lijuan Gao, ; Guobing Chen, ; Hongyi Zhang,
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Pribluda A, Daemen A, Lima AN, Wang X, Hafner M, Poon C, Modrusan Z, Katakam AK, Foreman O, Eastham J, Hung J, Haley B, Garcia JT, Jackson EL, Junttila MR. EHMT2 methyltransferase governs cell identity in the lung and is required for KRAS G12D tumor development and propagation. eLife 2022; 11:57648. [PMID: 35983994 PMCID: PMC9439681 DOI: 10.7554/elife.57648] [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: 04/07/2020] [Accepted: 08/16/2022] [Indexed: 11/30/2022] Open
Abstract
Lung development, integrity and repair rely on precise Wnt signaling, which is corrupted in diverse diseases, including cancer. Here, we discover that EHMT2 methyltransferase regulates Wnt signaling in the lung by controlling the transcriptional activity of chromatin-bound β-catenin, through a non-histone substrate in mouse lung. Inhibition of EHMT2 induces transcriptional, morphologic, and molecular changes consistent with alveolar type 2 (AT2) lineage commitment. Mechanistically, EHMT2 activity functions to support regenerative properties of KrasG12D tumors and normal AT2 cells—the predominant cell of origin of this cancer. Consequently, EHMT2 inhibition prevents KrasG12D lung adenocarcinoma (LUAD) tumor formation and propagation and disrupts normal AT2 cell differentiation. Consistent with these findings, low gene EHMT2 expression in human LUAD correlates with enhanced AT2 gene expression and improved prognosis. These data reveal EHMT2 as a critical regulator of Wnt signaling, implicating Ehmt2 as a potential target in lung cancer and other AT2-mediated lung pathologies.
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Affiliation(s)
- Ariel Pribluda
- Discovery Biology, Surrozen, South San Francisco, United States
| | - Anneleen Daemen
- Computational biology, Oric Pharma, South San Francisco, United States
| | - Anthony Nelson Lima
- Department of Translational Oncology, Genentech, Inc, South San Francisco, United States
| | - Xi Wang
- Department of Translational Oncology, Genentech, Inc, South San Francisco, United States
| | - Marc Hafner
- Department of Bioinformatics and Computational Biology, Genentech, Inc, South San Francisco, United States
| | - Chungkee Poon
- Department of Immunology, Genentech, Inc, South San Francisco, United States
| | - Zora Modrusan
- Department of Molecular Biology, Genentech, Inc, South San Francisco, United States
| | | | - Oded Foreman
- Department of Pathology, Genentech, Inc, South San Francisco, United States
| | - Jefferey Eastham
- Department of Pathology, Genentech, Inc, South San Francisco, United States
| | - Jefferey Hung
- Department of Pathology, Genentech, Inc, South San Francisco, United States
| | - Benjamin Haley
- Department of Molecular Biology, Genentech, Inc, South San Francisco, United States
| | - Julia T Garcia
- Department of Genetics, Stanford University, Stanford, United States
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44
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Parmar S, Easwaran H. Genetic and epigenetic dependencies in colorectal cancer development. Gastroenterol Rep (Oxf) 2022; 10:goac035. [PMID: 35975243 PMCID: PMC9373935 DOI: 10.1093/gastro/goac035] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/24/2022] [Accepted: 05/22/2022] [Indexed: 11/12/2022] Open
Abstract
Recent studies have mapped key genetic changes in colorectal cancer (CRC) that impact important pathways contributing to the multistep models for CRC initiation and development. In parallel with genetic changes, normal and cancer tissues harbor epigenetic alterations impacting regulation of critical genes that have been shown to play profound roles in the tumor initiation. Cumulatively, these molecular changes are only loosely associated with heterogenous transcriptional programs, reflecting the heterogeneity in the various CRC molecular subtypes and the paths to CRC development. Studies from mapping molecular alterations in early CRC lesions and use of experimental models suggest that the intricate dependencies of various genetic and epigenetic hits shape the early development of CRC via different pathways and its manifestation into various CRC subtypes. We highlight the dependency of epigenetic and genetic changes in driving CRC development and discuss factors affecting epigenetic alterations over time and, by extension, risk for cancer.
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Affiliation(s)
- Sehej Parmar
- Cancer Genetics and Epigenetics, Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hariharan Easwaran
- Cancer Genetics and Epigenetics, Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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45
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Chu S, Avery A, Yoshimoto J, Bryan JN. Genome wide exploration of the methylome in aggressive B-cell lymphoma in Golden Retrievers reveals a conserved hypermethylome. Epigenetics 2022; 17:2022-2038. [PMID: 35912844 PMCID: PMC9665123 DOI: 10.1080/15592294.2022.2105033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Few recurrent DNA mutations are seen in aggressive canine B cell lymphomas (cBCL), suggesting other frequent drivers. The methylated island recovery assay (MIRA-seq) or methylated CpG-binding domain sequencing (MBD-seq) was used to define the genome-wide methylation profiles in aggressive cBCL in Golden Retrievers to determine if cBCL can be better defined by epigenetic changes than by DNA mutations. DNA hypermethylation patterns were relatively homogenous within cBCL samples in Golden Retrievers, in different breeds and in geographical regions. Aberrant hypermethylation is thus suspected to be a central and early event in cBCL lymphomagenesis. Distinct subgroups within cBCL in Golden Retrievers were not identified with DNA methylation profiles. In comparison, the methylome profile of human DLBCL (hDLBCL) is relatively heterogeneous. Only moderate similarity between hDLBCL and cBCL was seen and cBCL likely cannot be accurately classified into the subtypes seen in hDLBCL. Genes with hypermethylated regions in the promoter-TSS-first exon of cBCL compared to normal B cells often also had additional hyper- and hypomethylated regions distributed throughout the gene suggesting non-randomized repeat targeting of key genes by epigenetic mechanisms. The prevalence of hypermethylation in transcription factor families in aggressive cBCL may represent a fundamental step in lymphomagenesis.
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Affiliation(s)
- Shirley Chu
- Department of Veterinary Medicine and Surgery, University of Missouri, 900 E. Campus Drive, Columbia, MO, USA
| | - Anne Avery
- Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA
| | - Janna Yoshimoto
- Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA
| | - Jeffrey N Bryan
- Department of Veterinary Medicine and Surgery, University of Missouri, 900 E. Campus Drive, Columbia, MO, USA
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46
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Zhou W, Hinoue T, Barnes B, Mitchell O, Iqbal W, Lee SM, Foy KK, Lee KH, Moyer EJ, VanderArk A, Koeman JM, Ding W, Kalkat M, Spix NJ, Eagleson B, Pospisilik JA, Szabó PE, Bartolomei MS, Vander Schaaf NA, Kang L, Wiseman AK, Jones PA, Krawczyk CM, Adams M, Porecha R, Chen BH, Shen H, Laird PW. DNA methylation dynamics and dysregulation delineated by high-throughput profiling in the mouse. CELL GENOMICS 2022; 2:100144. [PMID: 35873672 PMCID: PMC9306256 DOI: 10.1016/j.xgen.2022.100144] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 03/20/2022] [Accepted: 05/20/2022] [Indexed: 05/21/2023]
Abstract
We have developed a mouse DNA methylation array that contains 296,070 probes representing the diversity of mouse DNA methylation biology. We present a mouse methylation atlas as a rich reference resource of 1,239 DNA samples encompassing distinct tissues, strains, ages, sexes, and pathologies. We describe applications for comparative epigenomics, genomic imprinting, epigenetic inhibitors, patient-derived xenograft assessment, backcross tracing, and epigenetic clocks. We dissect DNA methylation processes associated with differentiation, aging, and tumorigenesis. Notably, we find that tissue-specific methylation signatures localize to binding sites for transcription factors controlling the corresponding tissue development. Age-associated hypermethylation is enriched at regions of Polycomb repression, while hypomethylation is enhanced at regions bound by cohesin complex members. Apc Min/+ polyp-associated hypermethylation affects enhancers regulating intestinal differentiation, while hypomethylation targets AP-1 binding sites. This Infinium Mouse Methylation BeadChip (version MM285) is widely accessible to the research community and will accelerate high-sample-throughput studies in this important model organism.
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Affiliation(s)
- Wanding Zhou
- Center for Computational and Genomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Corresponding author
| | - Toshinori Hinoue
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Bret Barnes
- Illumina, Inc., Bioinformatics and Instrument Software Department, San Diego, CA 92122, USA
| | - Owen Mitchell
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Waleed Iqbal
- Center for Computational and Genomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Sol Moe Lee
- Center for Computational and Genomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Kelly K. Foy
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Kwang-Ho Lee
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Ethan J. Moyer
- Center for Computational and Genomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Alexandra VanderArk
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Julie M. Koeman
- Genomics Core, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Wubin Ding
- Center for Computational and Genomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Manpreet Kalkat
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Nathan J. Spix
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Bryn Eagleson
- Vivarium and Transgenics Core, Van Andel Institute, Grand Rapids, MI 49503, USA
| | | | - Piroska E. Szabó
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Marisa S. Bartolomei
- Department of Cell and Developmental Biology, Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | | | - Liang Kang
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Ashley K. Wiseman
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Peter A. Jones
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Connie M. Krawczyk
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Marie Adams
- Genomics Core, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Rishi Porecha
- Illumina, Inc., Bioinformatics and Instrument Software Department, San Diego, CA 92122, USA
| | | | - Hui Shen
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
- Corresponding author
| | - Peter W. Laird
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
- Corresponding author
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47
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Conway K, Tsai YS, Edmiston SN, Parker JS, Parrish EA, Hao H, Kuan PF, Scott GA, Frank JS, Googe P, Ollila DW, Thomas NE. Characterization of the CpG Island Hypermethylated Phenotype Subclass in Primary Melanomas. J Invest Dermatol 2022; 142:1869-1881.e10. [PMID: 34843679 PMCID: PMC9135958 DOI: 10.1016/j.jid.2021.11.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/28/2021] [Accepted: 11/08/2021] [Indexed: 12/26/2022]
Abstract
Cutaneous melanoma can be lethal even if detected at an early stage. Epigenetic profiling may facilitate the identification of aggressive primary melanomas with unfavorable outcomes. We performed clustering of whole-genome methylation data to identify subclasses that were then assessed for survival, clinical features, methylation patterns, and biological pathways. Among 89 cutaneous primary invasive melanomas, we identified three methylation subclasses exhibiting low methylation, intermediate methylation, or hypermethylation of CpG islands, known as the CpG island methylator phenotype (CIMP). CIMP melanomas occurred as early as tumor stage 1b and, compared with low-methylation melanomas, were associated with age at diagnosis ≥65 years, lentigo maligna melanoma histologic subtype, presence of ulceration, higher American Joint Committee on Cancer stage and tumor stage, and lower tumor-infiltrating lymphocyte grade (all P < 0.05). Patients with CIMP melanomas had worse melanoma-specific survival (hazard ratio = 11.84; confidence interval = 4.65‒30.20) than those with low-methylation melanomas, adjusted for age, sex, American Joint Committee on Cancer stage, and tumor-infiltrating lymphocyte grade. Genes hypermethylated in CIMP compared with those in low-methylation melanomas included PTEN, VDR, PD-L1, TET2, and gene sets related to development/differentiation, the extracellular matrix, and immunity. CIMP melanomas exhibited hypermethylation of genes important in melanoma progression and tumor immunity, and although present in some early melanomas, CIMP was associated with worse survival independent of known prognostic factors.
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Affiliation(s)
- Kathleen Conway
- Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Dermatology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
| | - Yihsuan S Tsai
- Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Sharon N Edmiston
- Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Joel S Parker
- Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Genetics, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Eloise A Parrish
- Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Honglin Hao
- Department of Genetics, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Pei Fen Kuan
- Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, New York, USA
| | - Glynis A Scott
- Department of Dermatology, University of Rochester Medical Center, Rochester, New York, USA; Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Jill S Frank
- Department of Surgery, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Paul Googe
- Department of Dermatology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Pathology and Lab Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - David W Ollila
- Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Surgery, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Nancy E Thomas
- Department of Dermatology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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48
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Liu X, Liu X. PRC2, Chromatin Regulation, and Human Disease: Insights From Molecular Structure and Function. Front Oncol 2022; 12:894585. [PMID: 35800061 PMCID: PMC9255955 DOI: 10.3389/fonc.2022.894585] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/17/2022] [Indexed: 01/25/2023] Open
Abstract
Polycomb repressive complex 2 (PRC2) is a multisubunit histone-modifying enzyme complex that mediates methylation of histone H3 lysine 27 (H3K27). Trimethylated H3K27 (H3K27me3) is an epigenetic hallmark of gene silencing. PRC2 plays a crucial role in a plethora of fundamental biological processes, and PRC2 dysregulation has been repeatedly implicated in cancers and developmental disorders. Here, we review the current knowledge on mechanisms of cellular regulation of PRC2 function, particularly regarding H3K27 methylation and chromatin targeting. PRC2-related disease mechanisms are also discussed. The mode of action of PRC2 in gene regulation is summarized, which includes competition between H3K27 methylation and acetylation, crosstalk with transcription machinery, and formation of high-order chromatin structure. Recent progress in the structural biology of PRC2 is highlighted from the aspects of complex assembly, enzyme catalysis, and chromatin recruitment, which together provide valuable insights into PRC2 function in close-to-atomic detail. Future studies on the molecular function and structure of PRC2 in the context of native chromatin and in the presence of other regulators like RNAs will continue to deepen our understanding of the stability and plasticity of developmental transcriptional programs broadly impacted by PRC2.
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Bartlett TE, Evans I, Jones A, Barrett JE, Haran S, Reisel D, Papaikonomou K, Jones L, Herzog C, Pashayan N, Simões BM, Clarke RB, Evans DG, Ghezelayagh TS, Ponandai-Srinivasan S, Boggavarapu NR, Lalitkumar PG, Howell SJ, Risques RA, Rådestad AF, Dubeau L, Gemzell-Danielsson K, Widschwendter M. Antiprogestins reduce epigenetic field cancerization in breast tissue of young healthy women. Genome Med 2022; 14:64. [PMID: 35701800 PMCID: PMC9199133 DOI: 10.1186/s13073-022-01063-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 05/17/2022] [Indexed: 02/08/2023] Open
Abstract
Background Breast cancer is a leading cause of death in premenopausal women. Progesterone drives expansion of luminal progenitor cells, leading to the development of poor-prognostic breast cancers. However, it is not known if antagonising progesterone can prevent breast cancers in humans. We suggest that targeting progesterone signalling could be a means of reducing features which are known to promote breast cancer formation.
Methods In healthy premenopausal women with and without a BRCA mutation we studied (i) estrogen and progesterone levels in saliva over an entire menstrual cycle (n = 20); (ii) cancer-free normal breast-tissue from a control population who had no family or personal history of breast cancer and equivalently from BRCA1/2 mutation carriers (n = 28); triple negative breast cancer (TNBC) biopsies and healthy breast tissue taken from sites surrounding the TNBC in the same individuals (n = 14); and biopsies of ER+ve/PR+ve stage T1–T2 cancers and healthy breast tissue taken from sites surrounding the cancer in the same individuals (n = 31); and (iii) DNA methylation and DNA mutations in normal breast tissue (before and after treatment) from clinical trials that assessed the potential preventative effects of vitamins and antiprogestins (mifepristone and ulipristal acetate; n = 44).
Results Daily levels of progesterone were higher throughout the menstrual cycle of BRCA1/2 mutation carriers, raising the prospect of targeting progesterone signalling as a means of cancer risk reduction in this population. Furthermore, breast field cancerization DNA methylation signatures reflective of (i) the mitotic age of normal breast epithelium and (ii) the proportion of luminal progenitor cells were increased in breast cancers, indicating that luminal progenitor cells with elevated replicative age are more prone to malignant transformation. The progesterone receptor antagonist mifepristone reduced both the mitotic age and the proportion of luminal progenitor cells in normal breast tissue of all control women and in 64% of BRCA1/2 mutation carriers. These findings were validated by an alternate progesterone receptor antagonist, ulipristal acetate, which yielded similar results. Importantly, mifepristone reduced both the TP53 mutation frequency as well as the number of TP53 mutations in mitotic-age-responders. Conclusions These data support the potential usage of antiprogestins for primary prevention of poor-prognostic breast cancers. Trial registration Clinical trial 1 Mifepristone treatment prior to insertion of a levonorgestrel releasing intrauterine system for improved bleeding control – a randomized controlled trial, clinicaltrialsregister.eu, 2009-009014-40; registered on 20 July 2009. Clinical trial 2 The effect of a progesterone receptor modulator on breast tissue in women with BRCA1 and 2 mutations, clinicaltrials.gov, NCT01898312; registered on 07 May 2013. Clinical trial 3 A pilot prevention study of the effects of the anti- progestin Ulipristal Acetate (UA) on surrogate markers of breast cancer risk, clinicaltrialsregister.eu, 2015-001587-19; registered on 15 July 2015. Supplementary Information The online version contains supplementary material available at 10.1186/s13073-022-01063-5.
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Affiliation(s)
- Thomas E Bartlett
- Department of Statistical Science, University College London, London, WC1E 7HB, UK
| | - Iona Evans
- Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK
| | - Allison Jones
- Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK
| | - James E Barrett
- Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK.,European Translational Oncology Prevention and Screening (EUTOPS) Institute, Universität Innsbruck, 6060, Hall in Tirol, Austria.,Research Institute for Biomedical Aging Research, Universität Innsbruck, 6020, Innsbruck, Austria
| | - Shaun Haran
- Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK
| | - Daniel Reisel
- Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK
| | - Kiriaki Papaikonomou
- Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Louise Jones
- Centre for Tumour Biology Department, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Chiara Herzog
- European Translational Oncology Prevention and Screening (EUTOPS) Institute, Universität Innsbruck, 6060, Hall in Tirol, Austria.,Research Institute for Biomedical Aging Research, Universität Innsbruck, 6020, Innsbruck, Austria
| | - Nora Pashayan
- Department of Applied Health Research, University College London, 1-19 Torrington Place, London, WC1E 7HB, UK
| | - Bruno M Simões
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK, England
| | - Robert B Clarke
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK, England
| | - D Gareth Evans
- University of Manchester, St. Mary's Hospital, and University Hospital of South Manchester, Manchester, UK
| | - Talayeh S Ghezelayagh
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98195, USA.,Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, 98195, USA
| | - Sakthivignesh Ponandai-Srinivasan
- Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Nageswara R Boggavarapu
- Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Parameswaran G Lalitkumar
- Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Sacha J Howell
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK, England.,Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Rosa Ana Risques
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98195, USA
| | - Angelique Flöter Rådestad
- Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Louis Dubeau
- Department of Pathology, Keck School of Medicine, USC/Norris Comprehensive Cancer Centre, University of Southern California, Los Angeles, USA
| | - Kristina Gemzell-Danielsson
- Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Martin Widschwendter
- Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK. .,European Translational Oncology Prevention and Screening (EUTOPS) Institute, Universität Innsbruck, 6060, Hall in Tirol, Austria. .,Research Institute for Biomedical Aging Research, Universität Innsbruck, 6020, Innsbruck, Austria. .,Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
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50
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Liu C, Zhou X, Jin J, Zhu Q, Li L, Yin Q, Xu T, Gu W, Ma F, Yang R. The Association Between Breast Cancer and Blood-Based Methylation of CD160, ISYNA1 and RAD51B in the Chinese Population. Front Genet 2022; 13:927519. [PMID: 35812748 PMCID: PMC9261985 DOI: 10.3389/fgene.2022.927519] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 05/23/2022] [Indexed: 12/25/2022] Open
Abstract
Recent studies have identified DNA methylation signatures in the white blood cells as potential biomarkers for breast cancer (BC) in the European population. Here, we investigated the association between BC and blood-based methylation of cluster of differentiation 160 (CD160), inositol-3-phosphate synthase 1 (ISYNA1) and RAD51 paralog B (RAD51B) genes in the Chinese population. Peripheral blood samples were collected from two independent case-control studies with a total of 272 sporadic early-stage BC cases (76.5% at stage I&II) and 272 cancer-free female controls. Mass spectrometry was applied to quantitatively measure the levels of DNA methylation. The logistic regression and non-parametric tests were used for the statistical analyses. In contrast to the protective effects reported in European women, we reported the blood-based hypomethylation in CD160, ISYNA1 and RAD51B as risk factors for BC in the Chinese population (CD160_CpG_3, CD160_CpG_4/cg20975414, ISYNA1_CpG_2, RAD51B_CpG_3 and RAD51B_CpG_4; odds ratios (ORs) per -10% methylation ranging from 1.08 to 1.67, p < 0.05 for all). Moreover, hypomethylation of CD160, ISYNA1 and RAD51B was significantly correlated with age, BC subtypes including estrogen receptor (ER)-negative BC tumors, triple negative tumors, BC cases with larger size, advanced stages and more lymph node involvement. Our results supported the report in European women that BC is associated with altered methylation of CD160, ISYNA1 and RAD51B in the peripheral blood, although the effects are opposite in the Chinese population. The difference between the two populations may be due to variant genetic background or life styles, implicating that the validations of epigenetic biomarkers in variant ethnic groups are warranted.
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Affiliation(s)
- Chunlan Liu
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xiajie Zhou
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jialie Jin
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Qiang Zhu
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Lixi Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Qiming Yin
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Tian Xu
- Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Wanjian Gu
- Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Fei Ma
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Rongxi Yang
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
- *Correspondence: Rongxi Yang,
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