S Rodrı´guez-Rodero et al. Epigenetics and endocrine 21:4 R319–R330 Review cancer Epigenetic alterations in endocrine- related cancer Sandra Rodrı´guez-Rodero1,2, Elı´as Delgado-A´ lvarez1, Agustı´n F Ferna´ndez2, Juan L Ferna´ndez-Morera1, Edelmiro Mene´ndez-Torre1 and Mario F Fraga2,3 Correspondence 1Endocrinology and Nutrition Service, Hospital Universitario Central de Asturias, Av. Julian Claverı´a s/n, should be addressed 33006 Oviedo, Spain to E Mene´ ndez-Torre or 2Cancer Epigenetics Laboratory, Instituto Universitario de Oncologı´a del Principado de Asturias (IUOPA), M F Fraga Universidad de Oviedo, 33006 Oviedo, Spain Emails 3Department of Immunology and Oncology, National Center for Biotechnology, CNB-CSIC, Cantoblanco, [email protected] or Madrid E-28049, Spain [email protected] Abstract Aberrant epigenetics is a hallmark of cancer, and endocrine-related tumors are no exception. Key Words Recent research has been identifying an ever-growing number of epigenetic alterations in " multiple endocrine both genomic DNA methylation and histone post-translational modification in tumors of the neoplasias endocrine system. Novel microarray and ultra-deep sequencing technologies have allowed " neuroendocrine tumors the identification of genome-wide epigenetic patterns in some tumor types such as " oncology adrenocortical, parathyroid, and breast carcinomas. However, in other cancer types, such " pathogenesis as the multiple endocrine neoplasia syndromes and thyroid cancer, tumor information is limited to candidate genes alone. Future research should fill this gap and deepen our understanding of the functional role of these alterations in cancer, as well as defining Endocrine-Related Cancer their possible clinical uses. Endocrine-Related Cancer (2014) 21, R319–R330 Introduction Epigeneticsisdefinedasthestudyofthosestable However, all such mechanisms in fact cooperate with each genetic modifications that result in changes in function other, and also with other levels of regulation, to establish and gene expression without altering the DNA sequence. and maintain chromatin in either a condensate or non- The term was first described in 1942 by C H Waddington condensate state, which ultimately determines gene as the study of how genotypes give rise to phenotypes expression profiles. In this review, we focus exclusively through programmed changes during development on DNA methylation and histone modifications. (Waddington 1942). DNA methylation is the most studied epigenetic Epigenetic mechanisms refer to changes in the mechanism to date and occurs in w3% of cytosines, which interaction between DNA and histones, which influences precede guanines as part of the so-called cytosine–guanine the degree of compaction of chromatin, allowing the dinucleotides (CpGs) present in the genome (Hermann et al. genome to be differentially manifested depending on the 2004). Recently, non-CpG methylation in stem cells has stage of development, the type of tissue, or the existence been described and it seems not to be directly associated of disease. Among these mechanisms, DNA methylation with transcriptional repression, but rather to be associated and histone post-translational modifications coexist with with maintaining a pluripotent state (Lister et al.2009). histone variants, chromatin remodelers, small non-coding Some CpG sites in the genome are concentrated RNA molecules, and polycomb and trithorax complexes. on the so-called ‘CpG islands’ located around 200 bp http://erc.endocrinology-journals.org q 2014 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-13-0070 Printed in Great Britain Downloaded from Bioscientifica.com at 10/02/2021 12:27:58AM via free access Review S Rodrı´guez-Rodero et al. Epigenetics and endocrine 21:4 R320 cancer at several kb from the transcription start site of a gene and ADP-ribosylation. These are, in the majority, dynamic (Antequera 2003). These CpG islands are present in 60% and reversible changes. The enormous variety of potential of genes and are usually non-methylated, except in modifications and their possible combinations generate a those genes subject to genomic imprinting, X chromo- wide range of functional responses known as the ‘histone some inactivation, or tissue-specific repression (Antequera code’. Histones play a role in the establishment of 2003). By contrast, those CpG dinucleotides that are structural domains of chromatin and the regulation of scattered throughout the genome are more methylated DNA functions such as transcription, repair, replication, and located mainly in the bodies of genes, intergenic and condensation of chromosomes. Two of the best- regions, repetitive sequences, and transposons (Martin- studied modifications are the acetylation and methylation Subero 2011, Fedoriw et al. 2012). In the context of CpG of histones. The former is carried out by histone islands, DNA methylation is sometimes associated with acetyltransferases (HATs) and reversed by histone deace- transcriptional repression, this being an important tylases (HDACs), while the latter is thought to take place at mechanism of gene regulation. DNA methylation can the lysine and arginine residues and can incorporate one promote greater condensation of chromatin, preventing to three methyl groups for each residue (Zhang et al. 2012). the access of transcription machinery. It has been At the transcriptional level, the effect of methylation proposed that, when CpG sites are part of non-coding, varies as a function of its extent and the specific residue repetitive sequences and transposons, the role of affected and it is also involved in establishing chromatin methylation is to preserve chromosome stability by structural domains. The enzymes responsible for this preventing the reactivation of mobile elements and modification are known as histone methyltransferases maintain the integrity of chromosomes (Bird 2002). (HMTs), substrate specific, and employ SAMe as a donor of Through the maintenance of chromosomal stability methyl groups, while the reverse process is carried out by and the regulation of gene expression, DNA methylation histone demethylases (Li et al. 2012). is crucial for processes such as cell differentiation and embryonic development (Fedoriw et al. 2012). It is Epigenetic alterations in tumors of the carried out by a group of enzymes known as DNA endocrine system cytosine-5-methyltransferases (DNMTs), which transfer the methyl group from S-adenosylmethionine (SAMe) In the last 20 years, advances in the field of endocrine to the C5 position of cytosine. In mammals, five DNMTs oncology have enabled the genetic basis of some heredi- Endocrine-Related Cancer have been described, of which only three are active: tary endocrine tumors to be uncovered, and they have also DNMT1 is primarily involved in the maintenance of contributed to increasing knowledge of certain sporadic methylation patterns and has a preference for hemi- diseases, and consequently the development of new methylated DNA, which is frequently located at DNA diagnosis or treatment methods. In addition, the contri- replication sites during the cell cycle (S phase) (Qin et al. bution of epigenetic mechanisms in tumor development 2011). DNMT3A and DNMT3B are known as the ‘de novo has been widely described. DNMTs,’ as they seem to possess the ability to establish In this review, we focus on those endocrine tumors profiles of DNA methylation and do not discriminate where the role of certain epigenetic mechanisms (DNA between hemimethylated and unmethylated DNA methylation and histone modifications) has been demon- (Chedin 2011); although further studies have demon- strated. Endocrine tumors affect parts of the body that strated that both types of enzymes play a role in the secrete hormones and include adrenal gland tumor maintenance of methylation as well as in methylation- (adrenocortical carcinoma, ACC), islet cell tumors (gas- dependent repression of specific oncogenes in cancer trinoma, VIPoma, glucagonoma, and somatostatinoma), cells (Fernandez et al. 2012). These enzymes determine neuroendocrine tumors (such as pheochromocytoma), the overall methylation profiles in the early stages of parathyroid and thyroid carcinomas, among others. embryonic development in germ cells and cooperate in In the following sections, for the purpose of discussion, the establishment and maintenance of DNA methylation these endocrine tumors will be divided into those which profiles (Fatemi et al. 2002). are hereditary (multiple endocrine neoplasia (MEN) Histones have an amino-terminal tail consisting of 20– syndromes) and those which are sporadic (thyroid, 35 amino acid residues, with a highly conserved sequence parathyroid, breast and ovarian, prostate, adrenocortical, that is susceptible to modifications such as acetylation, and lung neuroendocrine tumors and pheochromo- methylation, phosphorylation, ubiquitination, sumoylation, cytoma, and paraganglioma). http://erc.endocrinology-journals.org q 2014 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-13-0070 Printed in Great Britain Downloaded from Bioscientifica.com at 10/02/2021 12:27:58AM via free access Review S Rodrı´guez-Rodero et al. Epigenetics and endocrine 21:4 R321 cancer Hereditary endocrine tumors proteins MLL2 (KMT2B), mixed lineage leukemia, and MLL (KMT2A)), which displays a histone H3 lysine 4 methyl- The MEN syndromes MEN syndromes predispose transferase activity. Trimethylated H3K4 is an epigenetic people to develop endocrine tumors. The major glands mark typically associated