DOI: http://dx.doi.org/10.22516/25007440.229 Review articles Epigenetics of Colorectal Cancer Carlos Humberto Afanador A.,1 Carlos Mario Muñetón Peña.1 1 Medical Genetics Unit of the Department of Abstract Pediatrics in the Faculty of Medicine at the University of Antioquia in Medellín, Colombia Colorectal cancer (CRC) has broad geographic distribution and affects millions of people throughout the Correspondence: Dr. Carlos Mario Muñetón world. It occurs sporadically in 80% of cases, but the rest have family histories. Epigenetic alterations such [email protected], [email protected]. as DNA methylation and modification of histones and non-coding RNA are involved in the development of this ......................................... disease. At present, these alterations have valuable potential as biomarkers for early detection of CRC and Received: 15-05-17 could be useful for diagnosis and determination of prognosis for individuals with CRC. The purpose of this Accepted: 22-01-18 review is to describe the main epigenetic mechanisms involved in colorectal cancer and the important roles they have in the development and progression of the disease. Keywords Colorectal cancer, epigenetics, DNA methylation, repair genes, tumor suppressor genes. INTRODUCTION tions in the APC and MLH1 genes predispose to heredi- tary-type CRC. (7-9) Several different genetic alterations Colorectal cancer (CRC) is considered to be a public are involved in onset and development of this disease. (10) health problem with a wide geographic distribution, accor- These alterations affect the expression of multiple genes, ding to the GLOBOCAN 2012 registry. (1) Currently, promoting the transformation of the normal mucosa of the CRC is the third most common cancer in men and women colon into a benign polyp which progresses to early ade- in the world. Its incidence is high in developed countries noma, then becomes intermediate, and finally progresses to but low in developing countries. (1, 2) Nevertheless, recent adenocarcinoma. (10) data from the International Agency for Research on Cancer Several molecular pathways are known to explain the (IARC) show increasing incidence and mortality rates in development of CRC. Initially, the classic model of progres- less developed countries. (3, 4) sion from adenoma to carcinoma was proposed by Fearon Incidence of CRC and CRC mortality rates have increa- and Vogelstein. (11) It is called the traditional or suppres- sed in Colombia in recent last decades. (5, 6) According sor pathway and involves deactivation of the APC and to figures from GLOBOCAN 2012 for Colombia, CRC TP53 tumor suppressor genes plus mutations in the KRAS, ranks fourth in incidence and mortality for both sexes. In DCC and SMAD oncogenes. (11) The second pathway is the most recent year, 4,107 new cases were diagnosed, most called a mutator and is related to mutations in the MLH1 of which were in advanced stages of the disease. (1) and MSH2 genes of the MMR repair system which induce The CRC occurs sporadically in about 80% of cases, but microsatellite instability (MSI) in tumor cells. (12) The the remaining 20% ​​have family histories. Germline muta- third pathway is epigenetic and consists of repression of 30 © 2018 Asociaciones Colombianas de Gastroenterología, Endoscopia digestiva, Coloproctología y Hepatología gene expression by methylation of the promoter region of HISTONE MODIFICATION the tumor suppressor or repair genes. (13) The term epigenetics was invented in 1942 by Conrad Hal On transcriptional control mechanism involves modifi- Waddington. It now describes the mechanisms that modify cations in histone proteins that are associated with DNA. the structure of chromatics and affect levels of gene expres- (15, 16) Post-translational covalent modifications in spe- sion without changes in the sequence of deoxyribonucleic cific regions of histones are known to be an epigenetic acid (DNA). These mechanisms include methylation, ace- mechanism that regulates and modifies the structure of tylation and hydroxylation of DNA, modification of histone- chromatin and are thought to be associated with the origin like proteins, remodeling of the chromatin structure and and progression of cancer. (16) changes in non-coding ribonucleic acids (RNA). Epigenetic Current knowledge of histone modifications in the develo- modifications can be induced by external and internal factors pment of cancer in humans is very limited. Histones are orga- that may have effects similar to those of pathogenic muta- nized in a cylindrical structure, and modifications commonly tions, since they can inactivate expression of various genes in occur in H2A, H2B, H3 and H4 which are part of a histone a specific tissue. This has been shown in the carcinogenesis octamer. (15, 16) The nucleosome is a unit composed of of various organs and is of great importance in the develo- approximately 150 to 200 base pairs of DNA that are arranged pment of cancer since these modifications affect expression around the nucleosomal histones. The N-terminal portion of of tumor suppressor genes of the DNA repair system. (14) each histone that emerges from this compact structure is the The purpose of this review is to describe the most impor- target at which post-translational modifications occur. The tant epigenetic modifications related to CRC and their main types of modifications are phosphorylation, glycosyla- possible use in clinical applications as biomarkers for early tion, ADP-ribosylation, ubiquitination, sumoylation and, most detection of CRC. commonly, acetylation and methylation (Figure 1). (15, 16) SGRGKQGGKARAKAKSRSSRAGLQFPVGRVVHRLLRKGNY H2A PEPAKSAPAPKKGSKKAVTKAQKKDSKKRKRSKSRKEDSYSV H2B ARTKQTARKSTGGKAPRKQLLATKAARKSAPATGGVKKPSH H3 SFRFKGGKGLGKGGAKRHRKVLRDNIQGITKPAIRRLAR H4 Phosphorylation Acetylation H3 H2A Lysine methylation with gene expression Methylation (arginine) Lysine methylation without gene expression H2B H4 Ubiquitination Figure 1. Main post-translational modifications in N-terminal histones residues. The four histone proteins (H2A, H2B, H3 and H4) have a cylindrical structure called the histone nucleus. Main covalent modifications are phosphorylation, acetylation, methylation and ubiquitination. The image shows the sequence of amino acids that make up the N-terminal residue of each histone and the place where each type of modification occurs. Epigenetics of Colorectal Cancer 31 Acetylation and methylation are the most studied epigene- NH tic modifications in cancer. Amino acid residues, certain types 2 N of modifications and the histone domain have been observed N CH to be associated with the development and progression of 3 N cancer. (16-18) In general, of all the epigenetic mechanisms, SAM SAH histone modifications are of great importance and are the object of many studies about the epigenetics of cancer. DNMT O The acetylation/deacetylation and methylation/deme- O thylation states of lysine and arginine residues among the N N histones are among the most studied and best understood modifications. In general, it is known that hypoacetylation Cytosine 5-methylcytosine represses gene expression; while hyperacetylation of histo- nes activates the transcription of genes. Acetylation in speci- Figure 2. Methylation of cytosine in carbon 5 by means of DNMT. This fic histone motifs destabilizes chromatin fiber which allows enzyme catalyzes the union of a methyl group CH3 in the carbon 5 of increased mobility of the nucleosomes in the chromosomes. the cytosine, using the S-adenosyl methionine (SAH) of the CH3 group In this state, transcription factors bind to DNA. (19) as a donor molecule. SAH: S-adenosyl L-homocysteine. Currently, it is known that the deacetylation of histone H3K9 is related to repression of E-cadherin transcription Among the modifications that occur in the genome, in the cells of colorectal tumors. Other studies report that methylation has important functions such as regulating the loss of E-cadherin expression by methylation and the processes of replication, transcription, DNA repair and gene subsequent loss of cell adhesion appear to be critical steps expression. In addition, this DNA modification is necessary in the ability of tumor cells to invade adjacent tissues and for permanent deactivation of certain regions with genes metastasize. Various studies have shown that expression of that are not expressed after embryonic development and this protein is null or very low in poorly differentiated car- for deactivation of the X chromosome. It is also essential for cinomas, including CRC. (20, 21) coordination of transcriptional processes during embryonic development and cell differentiation. (10) DNA METHYLATION HYPERMETHYLATION OF DNA IN COLORECTAL Regulation of gene expression is the product of interac- CANCER tion between transcription initiation factors and promoter sequences located before the start codon (ATG). In nor- DNA methylation has been studied extensively in various mal cells, 60% of the genes coding in humans, the promo- types of cancer. (19, 26, 27). Similarly, the association bet- ter region is rich in sequences of cytosine-guanine (C-G, ween hypermethylation of CpG islands located near the gene called CpG islands). (22) promoter region and deactivation of gene transcription is One mechanism for complete inhibition of gene expres- well known. This includes deactivation of tumor suppressor sion is methylation of the promoter regions which pre- gene transcription, and these genes regulate the cell cycle and vents of transcription factors from