DOCSLIB.ORG

Epigenetic Inactivation of the P53-Induced Long Noncoding RNA

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Epigenetic Inactivation of the P53-Induced Long Noncoding RNA Epigenetic inactivation of the p53-induced long PNAS PLUS noncoding RNA TP53 target 1 in human cancer Angel Diaz-Lagaresa, Ana B. Crujeirasa,b,c, Paula Lopez-Serraa, Marta Solera, Fernando Setiena, Ashish Goyald,e, Juan Sandovala, Yutaka Hashimotoa, Anna Martinez-Cardúsa, Antonio Gomeza, Holger Heyna, Catia Moutinhoa, Jesús Espadaf,g, August Vidalh, Maria Paúlesh, Maica Galáni, Núria Salaj, Yoshimitsu Akiyamak, María Martínez-Iniestal, Lourdes Farrél,m, Alberto Villanueval, Matthias Grossd,e, Sven Diederichsd,e,n,o,p, Sonia Guila,1, and Manel Estellera,q,r,1 aCancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain; bCentro de Investigación Biomédica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto Salud Carlos III, 28029 Madrid, Spain; cEndocrine Division, Complejo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain; dDivision of RNA Biology and Cancer (B150), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; eInstitute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; fExperimental Dermatology and Skin Biology Group, Ramón y Cajal Institute for Biomedical Research (IRYCIS), Ramón y Cajal University Hospital, 28034 Madrid, Spain; gBionanotechnology Laboratory, Bernardo O’Higgins University, Santiago 8370854, Chile; hPathology Department, Hospital Universitari de Bellvitge, IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, Catalonia, Spain; iDepartment of Medical Oncology, Catalan Institute of Oncology (ICO), IDIBELL, L’Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain; jUnit of Nutrition and Cancer, Cancer Epidemiology Research Program, ICO, IDIBELL, 08908 Barcelona, Catalonia, Spain; kDepartment of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-8510 Tokyo, Japan; lProgram Against Cancer Therapeutic Resistance (ProCURE), ICO, IDIBELL, L’Hospitalet del Llobregat, 08908 Barcelona, Catalonia, Spain; mLaboratory of Experimental Pathology (LAPEX), Gonçalo Moniz Research Center, Oswaldo Cruz Foundation (CPQGM/ FIOCRUZ) and National Institute of Science and Technology of Tropical Diseases (INCT/DT), 40296710 Salvador, Bahia, Brazil; nDivision of Cancer Research, Department of Thoracic Surgery, Medical Center–University of Freiburg, 79106 Freiburg, Germany; oFaculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; pGerman Cancer Consortium (DKTK), 79106 Freiburg, Germany; qDepartament de Ciències Fisiològiques II, Escola de Medicina, Universitat de Barcelona, 08907 Barcelona, Catalonia, Spain; and rInstitució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Catalonia, Spain Edited by Mariano Barbacid, Spanish National Cancer Research Center (CNIO), Madrid, Spain, and approved October 12, 2016 (received for review May 27, 2016) Long noncoding RNAs (lncRNAs) are important regulators of cellular MALAT1 (15), or as tumor suppressors, such as LincRNA-p21 (16) homeostasis. However, their contribution to the cancer phenotype and Uc.283+A (17). still needs to be established. Herein, we have identified a p53- Several recent studies have demonstrated that lncRNAs are induced lncRNA, TP53TG1, that undergoes cancer-specific promoter deregulated in cancer tissues. Causes of this deregulation include hypermethylation-associated silencing. In vitro and in vivo assays genetic events leading to abnormal expression, such as copy identify a tumor-suppressor activity for TP53TG1 and a role in the p53 number alterations or single-nucleotide polymorphisms located in response to DNA damage. Importantly, we show that TP53TG1 binds lncRNA promoter regions (8–11). However, another possibility is to the multifaceted DNA/RNA binding protein YBX1 to prevent its that lncRNAs may themselves be targets of epigenetic disruption. nuclear localization and thus the YBX1-mediated activation of onco- In this regard, the promoter CpG island hypermethylation-asso- genes. TP53TG1 epigenetic inactivation in cancer cells releases the ciated silencing of coding tumor-suppressor genes and micro- transcriptional repression of YBX1-targeted growth-promoting genes RNAs is a well-established hallmark of human cancer (18–21). and creates a chemoresistant tumor. TP53TG1 hypermethylation in In recent times, a relatively small number of lncRNAs, such as primary tumors is shown to be associated with poor outcome. The epigenetic loss of TP53TG1 therefore represents an altered event in an Significance lncRNA that is linked to classical tumoral pathways, such as p53 sig- naling, but is also connected to regulatory networks of the cancer cell. Long noncoding RNAs (lncRNAs) are starting to be recognized as critical molecules for cellular transformation, although only DNA methylation | long noncoding RNA | epigenetics | cancer a few candidates have so far been characterized. Here we re- port that TP53TG1 is an lncRNA that is critical for the correct t has been estimated that only 2% of the genome is transcribed response of p53 to DNA damage. The cancer growth suppres- Iinto protein-coding RNAs (1), so most of the transcriptome sor features of TP53TG1 are linked to its ability to block the corresponds to noncoding transcripts, which are classified tumorigenic activity of the RNA binding protein YBX1. The DNA according to their length and structural properties (2, 3). Among methylation-associated silencing of TP53TG1 produces aggres- the small noncoding RNAs (ncRNAs), the abundant class of sive tumors that are resistant to cellular death when DNA- miRNAs (19–25 nt) regulates gene expression through interac- damaging agents and small targeted molecules are used. Our tions based on their complementarity with target mRNAs (4). study provides an example of a tumor suppressor lncRNA un- These ncRNAs have been widely studied in the context of cancer dergoing an epigenetic lesion in cancer that is placed at the cells (5, 6). The other main group of ncRNAs is the long ncRNAs crossroads of DNA damage and oncogenic pathways. (lncRNAs; arbitrarily >200 nt), which are defined as lacking Author contributions: A.D.-L., S.G., and M.E. designed research; A.D.-L., A.B.C., P.L.-S., protein-coding potential but otherwise often display mRNA-like M.S., F.S., A. Goyal, J.S., Y.H., A.M.-C., A. Gomez, H.H., C.M., J.E., A. Vidal, M.P., M. Galan, properties, including multiexonic gene structures and poly(A) tails N.S., Y.A., M.M.-I., L.F., A. Villanueva, M. Gross, S.D., and S.G. performed research; A.D.-L., (2, 3). LncRNAs are associated with a variety of regulatory functions, A.B.C., P.L.-S., M.S., F.S., A. Goyal, J.S., Y.H., A.M.-C., A. Gomez, H.H., C.M., J.E., A. Vidal, M.P., M. Galan, N.S., Y.A., M.M.-I., L.F., A. Villanueva, M. Gross, S.D., S.G., and M.E. ana- including chromatin-related roles, splicing control, and transcrip- lyzed data; and A.D.-L., S.G., and M.E. wrote the paper. tional regulation (7–9). Despite recent reports describing aberrant The authors declare no conflict of interest. expression of lncRNAs in human tumors (8–11), few of these mol- This article is a PNAS Direct Submission. ecules have been carefully characterizedwithrespecttotheirfunc- Freely available online through the PNAS open access option. tional roles in the promotion or inhibition of carcinogenesis (12, 1To whom correspondence may be addressed. Email: [email protected] or sguil@ 13). However, significant exceptions exist, and mechanisms of idibell.cat. action and downstream cellular effects have been demonstrated This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. MEDICAL SCIENCES for lncRNAs acting as oncogenes, such as HOTAIR (14) and 1073/pnas.1608585113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1608585113 PNAS | Published online November 7, 2016 | E7535–E7544 Downloaded by guest on September 24, 2021 transcribed–ultraconserved regions (22), antisense RNAs (23), DNA methyltransferase 1 (DNMT1) and DNMT3b (double knock- and small nucleolar RNAs (24), have been shown to undergo out, DKO) (25). DKO cells have drastically reduced DNMT activity, cancer-specific epigenetic inactivation, but the field of DNA 5-methylcytosine DNA content, and, above all, a release of coding methylation-dependent silencing of lncRNAs remains largely un- genes and microRNA silencing associated with promoter CpG island explored. In this study, we have found that the epigenetic loss of hypomethylation (25). We wanted to identify cancer-specific DNA the lncRNA TP53TG1 enhances tumor progression, prevents an methylation events in lncRNA loci, so we also included two samples effective p53 response to DNA damage, creates a chemoresistant of normal colon mucosa in our study design. We obtained the phenotype, and unleashes the transforming capacities of its part- DNA methylation profile of the wild-type HCT-116 cells, the derived ner, identified herein, the RNA binding protein YBX1. DKO cells, and the aforementioned normal colon using the Infinium HumanMethylation450 (450K) microarray, which interrogates 482,422 Results CpG sites (26). Noting that the platform includes 104 annotated TP53TG1 Shows Cancer-Specific DNA Methylation-Associated Transcriptional lncRNAs with a 5′-CpG island (SI Appendix,TableS1)enabledusto Silencing. To characterize cancer-specific DNA methylation changes narrow our search to the candidate methylated positions with a possible that affect lncRNA expression, we followed the experimental work-
Load more

Recommended publications
  • Interplay Between P53 and Epigenetic Pathways in Cancer
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2016 Interplay Between P53 and Epigenetic Pathways in Cancer Jiajun Zhu University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Biology Commons, Cell Biology Commons, and the Molecular Biology Commons Recommended Citation Zhu, Jiajun, "Interplay Between P53 and Epigenetic Pathways in Cancer" (2016). Publicly Accessible Penn Dissertations. 2130. https://repository.upenn.edu/edissertations/2130 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2130 For more information, please contact [email protected]. Interplay Between P53 and Epigenetic Pathways in Cancer Abstract The human TP53 gene encodes the most potent tumor suppressor protein p53. More than half of all human cancers contain mutations in the TP53 gene, while the majority of the remaining cases involve other mechanisms to inactivate wild-type p53 function. In the first part of my dissertation research, I have explored the mechanism of suppressed wild-type p53 activity in teratocarcinoma. In the teratocarcinoma cell line NTera2, we show that wild-type p53 is mono-methylated at Lysine 370 and Lysine 382. These post-translational modifications contribute ot the compromised tumor suppressive activity of p53 despite a high level of wild-type protein in NTera2 cells. This study provides evidence for an epigenetic mechanism that cancer cells can exploit to inactivate p53 wild-type function. The paradigm provides insight into understanding the modes of p53 regulation, and can likely be applied to other cancer types with wild-type p53 proteins. On the other hand, cancers with TP53 mutations are mostly found to contain missense substitutions of the TP53 gene, resulting in expression of full length, but mutant forms of p53 that confer tumor-promoting “gain-of-function” (GOF) to cancer.
    [Show full text]
  • Genomic and Epigenomic EBF1 Alterations Modulate TERT Expression in Gastric Cancer
    Genomic and epigenomic EBF1 alterations modulate TERT expression in gastric cancer Manjie Xing, … , Bin Tean Teh, Patrick Tan J Clin Invest. 2020;130(6):3005-3020. https://doi.org/10.1172/JCI126726. Research Article Gastroenterology Oncology Graphical abstract Find the latest version: https://jci.me/126726/pdf The Journal of Clinical Investigation RESEARCH ARTICLE Genomic and epigenomic EBF1 alterations modulate TERT expression in gastric cancer Manjie Xing,1,2,3 Wen Fong Ooi,2 Jing Tan,4,5 Aditi Qamra,2,3 Po-Hsien Lee,6 Zhimei Li,5 Chang Xu,1,6 Nisha Padmanabhan,1 Jing Quan Lim,7 Yu Amanda Guo,8 Xiaosai Yao,9 Mandoli Amit,1 Ley Moy Ng,6 Taotao Sheng,1,10 Jing Wang,1 Kie Kyon Huang,1 Chukwuemeka George Anene-Nzelu,11,12 Shamaine Wei Ting Ho,1,6 Mohana Ray,13 Lijia Ma,13 Gregorio Fazzi,14 Kevin Junliang Lim,1 Giovani Claresta Wijaya,5 Shenli Zhang,1 Tannistha Nandi,2 Tingdong Yan,1 Mei Mei Chang,8 Kakoli Das,1 Zul Fazreen Adam Isa,2 Jeanie Wu,1 Polly Suk Yean Poon,2 Yue Ning Lam,2 Joyce Suling Lin,2 Su Ting Tay,1 Ming Hui Lee,1 Angie Lay Keng Tan,1 Xuewen Ong,1 Kevin White,13,15 Steven George Rozen,1,16 Michael Beer,17,18 Roger Sik Yin Foo,11,12 Heike Irmgard Grabsch,14,19 Anders Jacobsen Skanderup,8 Shang Li,1,20 Bin Tean Teh,1,5,6,9,16,20 and Patrick Tan1,2,6,16,21,22,23 1Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
    [Show full text]
  • Epigenetics Changes in Breast Cancer
    ering & B ne io gi m n e e d io i c B a f l Behera P, J Bioengineer & Biomedical Sci 2017, S Journal of o l c a i e n n r 7:2 c u e o J DOI: 10.4172/2155-9538.1000223 ISSN: 2155-9538 Bioengineering & Biomedical Science Review Article Open Access Epigenetics Changes in Breast Cancer: Current Aspects in India Behera P* Department of Biotechnology, Amity University, Lucknow, India *Corresponding author: Behera P, Department of Biotechnology, Amity University, Lucknow, India, Tel: 9703466651; E-mail: [email protected] Received date: March 25, 2017; Accepted date: April 4, 2017; Published date: April 15, 2017 Copyright: © 2017 Behera P. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited. Abstract Epigenetics is turning out to be one of the promising studies in cancer research. This review focuses mainly on how genetic and epigenetic factors like DNA methylation, histone modifications and various other genes can assess the promoter region of cancer related genes and provides a tool for cancer diagnosis and research. The objective of the review is to provide an overview of the literature with some recent developments providing insights into the important question of co-evolution of epigenetic changes in breast cancer progression and tumorigenesis. This review also comply study of different genetic changes existing in breast cancer. Further in this review focus on functioning of DNA methylation, including both normal, disruptions or abnormal role in human disease, and changes in DNA methylation during human breast cancer is also noted.
    [Show full text]
  • Epigenetics in Inflammatory Breast Cancer: Biological Features And
    cells Review Epigenetics in Inflammatory Breast Cancer: Biological Features and Therapeutic Perspectives Flavia Lima Costa Faldoni 1,2 , Cláudia Aparecida Rainho 3 and Silvia Regina Rogatto 4,* 1 Department of Gynecology and Obstetrics, Medical School, São Paulo State University (UNESP), Botucatu 18618-687, São Paulo, Brazil; fl[email protected] 2 Hermínio Ometto Foundation, Araras 13607-339, São Paulo, Brazil 3 Department of Chemical and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-689, São Paulo, Brazil; [email protected] 4 Department of Clinical Genetics, Lillebaelt University Hospital of Southern Denmark, Institute of Regional Health Research, University of Southern Denmark, 7100 Odense, Denmark * Correspondence: [email protected]; Tel.: +45-79-4066-69 Received: 31 March 2020; Accepted: 30 April 2020; Published: 8 May 2020 Abstract: Evidence has emerged implicating epigenetic alterations in inflammatory breast cancer (IBC) origin and progression. IBC is a rare and rapidly progressing disease, considered the most aggressive type of breast cancer (BC). At clinical presentation, IBC is characterized by diffuse erythema, skin ridging, dermal lymphatic invasion, and peau d’orange aspect. The widespread distribution of the tumor as emboli throughout the breast and intra- and intertumor heterogeneity is associated with its poor prognosis. In this review, we highlighted studies documenting the essential roles of epigenetic mechanisms in remodeling chromatin and modulating gene expression during mammary gland differentiation and the development of IBC. Compiling evidence has emerged implicating epigenetic changes as a common denominator linking the main risk factors (socioeconomic status, environmental exposure to endocrine disruptors, racial disparities, and obesity) with IBC development.
    [Show full text]
  • Genetics, Epigenetics and Cancer. Cancer Therapy
    Cancer Therapy & Oncology International Journal ISSN: 2473-554X Research Article Canc Therapy & Oncol Int J Volume 4 Issue 2 - April 2017 Copyright © All rights are reserved by Alain L. Fymat DOI: 10.19080/CTOIJ.2017.04.555634 Genetics, Epigenetics and Cancer Alain L. Fymat* International Institute of Medicine and Science, USA Submission: March 27, 2017; Published: April 07, 2017 *Correspondence Address: Alain L. Fymat, International Institute of Medicine and Science, USA, Tel: ; Email: Abstract With deeper understanding of cell biology and genetics, it now appears that cancer is less an organ disease and more a disease of the genes that regulate cell growth and differentiation are altered. Most cancers have multiple possible concurring causes, and it is not possiblemolecular to mechanisms prevent all such caused causes. by mutations However, ofonly specific a small genes. minority Cancer of cancersis fundamentally (5-10%) are a disease due to ofinherited tissue growth genetic regulation mutations failurewhereas when the vast majority (90-95%) are non-hereditary epigenetic mutations that are caused by various agents (environmental factors, physical factors, and hormones). Thus, although there are some genetic predispositions in a small fraction of cancers, the major fraction is due to a set of new genetic mutations (called “epigenetic” mutations). After a brief primer on cancer and its genetics, this article focuses on the epigenetics of cancer. Epigenetics is the study of cellular and physiological traits inherited by daughter cells, but not caused by changes in the DNA sequence. imprintingImportant examplesand trans-generational of epigenetic mechanisms inheritance. (DNAEpigenetic methylation, carcinogens histone and modification, cancer treatment chromatin are also remodeling) treated.
    [Show full text]
  • Cancer Epigenetics Drug Discovery and Development: the Challenge of Hitting the Mark
    Amendment history: Corrigendum (March 2014) Cancer epigenetics drug discovery and development: the challenge of hitting the mark Robert M. Campbell, Peter J. Tummino J Clin Invest. 2014;124(1):64-69. https://doi.org/10.1172/JCI71605. Review Series Over the past several years, there has been rapidly expanding evidence of epigenetic dysregulation in cancer, in which histone and DNA modification play a critical role in tumor growth and survival. These findings have gained the attention of the drug discovery and development community, and offer the potential for a second generation of cancer epigenetic agents for patients following the approved “first generation” of DNA methylation (e.g., Dacogen, Vidaza) and broad- spectrum HDAC inhibitors (e.g., Vorinostat, Romidepsin). This Review provides an analysis of prospects for discovery and development of novel cancer agents that target epigenetic proteins. We will examine key examples of epigenetic dysregulation in tumors as well as challenges to epigenetic drug discovery with emerging biology and novel classes of drug targets. We will also highlight recent successes in cancer epigenetics drug discovery and consider important factors for clinical success in this burgeoning area. Find the latest version: https://jci.me/71605/pdf Review series Cancer epigenetics drug discovery and development: the challenge of hitting the mark Robert M. Campbell1 and Peter J. Tummino2 1Oncology Drug Discovery, Eli Lilly and Company, Lily Corporate Center, Indianapolis, Indiana, USA. 2Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania, USA. Over the past several years, there has been rapidly expanding evidence of epigenetic dysregulation in cancer, in which histone and DNA modification play a critical role in tumor growth and survival.
    [Show full text]
  • Cancer Epigenetics: from Mechanism to Therapy
    Leading Edge Review Cancer Epigenetics: From Mechanism to Therapy Mark A. Dawson1,2 and Tony Kouzarides1,* 1Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK 2Department of Haematology, Cambridge Institute for Medical Research and Addenbrooke’s Hospital, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cell.2012.06.013 The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15 years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated target- ing regulate many biological processes that are fundamental to the genesis of cancer. Here, we present the basic principles behind these epigenetic pathways and highlight the evidence suggest- ing that their misregulation can culminate in cancer. This information, along with the promising clin- ical and preclinical results seen with epigenetic drugs against chromatin regulators, signifies that it is time to embrace the central role of epigenetics in cancer. Chromatin is the macromolecular complex of DNA and histone The information conveyed by epigenetic modifications plays proteins, which provides the scaffold for the packaging of our a critical role in the regulation of all DNA-based processes, entire genome. It contains the heritable material of eukaryotic such as transcription, DNA repair, and replication. Conse- cells. The basic functional unit of chromatin is the nucleosome. quently, abnormal expression patterns or genomic alterations It contains 147 base pairs of DNA, which is wrapped around in chromatin regulators can have profound results and can a histone octamer, with two each of histones H2A, H2B, H3, lead to the induction and maintenance of various cancers.
    [Show full text]
  • Genome-Wide Profiling of P53-Regulated Enhancer Rnas
    ARTICLE Received 29 Aug 2014 | Accepted 4 Feb 2015 | Published 27 Mar 2015 DOI: 10.1038/ncomms7520 OPEN Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA Nicolas Le´veille´1,*, Carlos A. Melo1,2,*, Koos Rooijers1,*, Angel Dı´az-Lagares3, Sonia A. Melo4, Gozde Korkmaz1, Rui Lopes1, Farhad Akbari Moqadam5, Ana R. Maia6, Patrick J. Wijchers7, Geert Geeven7, Monique L. den Boer5, Raghu Kalluri4, Wouter de Laat7, Manel Esteller3,8,9 & Reuven Agami1,10 p53 binds enhancers to regulate key target genes. Here, we globally mapped p53-regulated enhancers by looking at enhancer RNA (eRNA) production. Intriguingly, while many p53- induced enhancers contained p53-binding sites, most did not. As long non-coding RNAs (lncRNAs) are prominent regulators of chromatin dynamics, we hypothesized that p53- induced lncRNAs contribute to the activation of enhancers by p53. Among p53-induced lncRNAs, we identified LED and demonstrate that its suppression attenuates p53 function. Chromatin-binding and eRNA expression analyses show that LED associates with and acti- vates strong enhancers. One prominent target of LED was located at an enhancer region within CDKN1A gene, a potent p53-responsive cell cycle inhibitor. LED knockdown reduces CDKN1A enhancer induction and activity, and cell cycle arrest following p53 activation. Finally, promoter-associated hypermethylation analysis shows silencing of LED in human tumours. Thus, our study identifies a new layer of complexity in the p53 pathway and suggests its dysregulation in cancer. 1 Division of Biological Stress Response, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. 2 Doctoral Programme in Biomedicine and Experimental Biology, Centre for Neuroscience and Cell Biology, Coimbra University, 3004-504 Coimbra, Portugal.
    [Show full text]
  • Inherited BRCA1 Epimutation As a Novel Cause of Breast and Ovarian Cancer
    bioRxiv preprint doi: https://doi.org/10.1101/246934; this version posted January 18, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Inherited BRCA1 epimutation as a novel cause of breast and ovarian cancer D. Gareth R. Evans M.D.1-4,*, Elke M. van Veen M.Sc.1,5,*, Helen J. Byers B.Sc.1,5, Andrew J. Wallace Ph.D.5, Jamie M. Ellingford Ph.D.1,5, Glenda Beaman Ph.D.1,5, Javier Santoyo-Lopez Ph.D.6, Timothy J. Aitman D.Phil. 6, Diana M. Eccles M.D.7, Fiona I. Lalloo M.D.5, Miriam J. Smith Ph.D.1,5,* & William G. Newman Ph.D.1,4,5,*. 1 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PL, UK. 2 Prevention Breast Cancer Centre and Nightingale Breast Screening Centre, University Hospital of South Manchester, Manchester, M23 9LT, UK. 3 The Christie NHS Foundation Trust, Manchester, M20 4BX, UK. 4 Manchester Breast Centre, Manchester Cancer Research Centre, University of Manchester, M20 4BX, Manchester, UK. 5 Manchester Centre for Genomic Medicine, St. Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK. 6Centre for Genomic and Experimental Medicine, and Edinburgh Genomics, University of Edinburgh, Edinburgh, EH4 2XU, UK 7Cancer Sciences Academic Unit and Southampton Clinical Trials Unit, Faculty of Medicine, University of Southampton and University Hospital Southampton Foundation Trust, Southampton, UK.
    [Show full text]
  • The Role of H3K4 Trimethylation in Cpg Islands Hypermethylation in Cancer
    biomolecules Review The Role of H3K4 Trimethylation in CpG Islands Hypermethylation in Cancer Giuseppe Zardo Department of Experimental Medicine, School of Pharmacy and Medicine, University of Rome “Sapienza”, 00161 Rome, Italy; [email protected] Abstract: CpG methylation in transposons, exons, introns and intergenic regions is important for long- term silencing, silencing of parasitic sequences and alternative promoters, regulating imprinted gene expression and determining X chromosome inactivation. Promoter CpG islands, although rich in CpG dinucleotides, are unmethylated and remain so during all phases of mammalian embryogenesis and development, except in specific cases. The biological mechanisms that contribute to the maintenance of the unmethylated state of CpG islands remain elusive, but the modification of established DNA methylation patterns is a common feature in all types of tumors and is considered as an event that intrinsically, or in association with genetic lesions, feeds carcinogenesis. In this review, we focus on the latest results describing the role that the levels of H3K4 trimethylation may have in determining the aberrant hypermethylation of CpG islands in tumors. Keywords: H3K4 trimethylation; DNA hypermethylation; acute myeloid leukemia; cancer 1. Histone Lysine Methylation Epigenetic landscapes functionally define the chromatin architecture and they are Citation: Zardo, G. The Role of shaped by the coordinated activity of “writers”, “readers” and “erasers”. “Writers” intro- H3K4 Trimethylation in CpG Islands duce covalent chemical modifications into DNA and histone tails, the “erasers” modulate Hypermethylation in Cancer. the amount of these modifications and the “readers” recognize and bind the chemical Biomolecules 2021, 11, 143. https:// modifications which induce functional effects in the chromatin architecture and DNA bind- doi.org/10.3390/biom11020143 ing of transcription factors (TFs).
    [Show full text]
  • Telomerase Reverse Transcriptase (TERT) in Action: Cross-Talking with Epigenetics
    International Journal of Molecular Sciences Review Telomerase Reverse Transcriptase (TERT) in Action: Cross-Talking with Epigenetics Xiaotian Yuan 1,2,* and Dawei Xu 2,3,* 1 School of Medicine, Shandong University, Jinan 250012, China 2 Department of Medicine, Center for Molecular Medicine (CMM) and Bioclinicum, Karolinska Institute and Karolinska University Hospital Solna, 171 64 Solna, Sweden 3 Shandong University-Karolinska Institute Collaborative Laboratory for Cancer and Stem Cell Research, Jinan 250033, China * Correspondence: [email protected] (X.Y.); [email protected] (D.X.) Received: 18 June 2019; Accepted: 4 July 2019; Published: 7 July 2019 Abstract: Telomerase, an RNA-dependent DNA polymerase with telomerase reverse transcriptase (TERT) as the catalytic component, is silent due to the tight repression of the TERT gene in most normal human somatic cells, whereas activated only in small subsets of cells, including stem cells, activated lymphocytes, and other highly proliferative cells. In contrast, telomerase activation via TERT induction is widespread in human malignant cells, which is a prerequisite for malignant transformation. It is well established that TERT/telomerase extends telomere length, thereby conferring sustained proliferation capacity to both normal and cancerous cells. The recent evidence has also accumulated that TERT/telomerase may participate in the physiological process and oncogenesis independently of its telomere-lengthening function. For instance, TERT is shown to interact with chromatin remodeling factors and to regulate DNA methylation, through which multiple cellular functions are attained. In the present review article, we summarize the non-canonical functions of TERT with a special emphasis on its cross-talk with epigenetics: How TERT contributes to epigenetic alterations in physiological processes and cancer, and how the aberrant epigenetics in turn facilitate TERT expression and function, eventually promoting cancer either initiation or progression or both.
    [Show full text]
  • Identification of Endometrial Cancer Methylation Features Using a Combined
    Identification of endometrial cancer methylation features using a combined methylation analysis method DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Michael P Trimarchi B.S. Biomedical Sciences Graduate Program The Ohio State University 2016 Dissertation Committee: Joanna L Groden, Advisor Paul Goodfellow Ralf A. Bundschuh Jeffrey Parvin Pearlly Yan Copyrighted by Michael P Trimarchi 2016 Abstract Introduction: DNA methylation is a stable epigenetic mark that is frequently altered in tumors. DNA methylation marks are attractive biomarkers for disease states given the stability of DNA methylation in living cells and in biologic specimens. Widespread accumulation of methylation in regulatory elements in some cancers (termed the CpG island methylator phenotype, CIMP) can play an important role in tumorigenesis. High resolution assessment of CIMP for the entire genome, however, remains cost prohibitive and requires quantities of DNA that are not available for many tissue samples of interest. Genome-wide scans of methylation have been undertaken for large numbers of tumors, and higher resolution analyses have been performed for a limited number of cancer specimens. Yet methods for analyzing these large datasets and integrating findings from different studies have not been fully developed. An approach was developed to profile CIMP by combining the strengths of two different methylome profiling techniques. Methods: Methylomes for 76 primary endometrial cancer and 12 normal endometrial samples were generated using methylated fragment capture and second generation sequencing (MethylCap-seq). Publically available data from The Cancer Genome Atlas (TCGA) for 203 endometrial cancers, analyzed using the Infinium HumanMethylation 450 beadchip, were compared to the MethylCap-seq data.
    [Show full text]