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DNA Methylation and Histone Modifications As Epigenetic Regulation in Prostate Cancer (Review)

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DNA Methylation and Histone Modifications As Epigenetic Regulation in Prostate Cancer (Review) ONCOLOGY REPORTS 38: 2587-2596, 2017 DNA methylation and histone modifications as epigenetic regulation in prostate cancer (Review) MARIA NOWACKA-ZAWISZA and EWELINA WIŚNIK Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland Received March 15, 2017; Accepted July 24, 2017 DOI: 10.3892/or.2017.5972 Abstract. Prostate cancer is the second most commonly 1. Introduction diagnosed cancer in men in Poland after lung cancer and the third leading cause of cancer-related mortality after lung and Prostate cancer (PC) is one of the most frequently diagnosed colon cancer. The etiology of most cases of prostate cancer cancers in men. One cause for neoplastic transformation are not fully known, and therefore it is essential to search for is abnormal gene expression, which is not determined by the molecular basis of prostate cancer and markers for the nucleotide sequence changes in DNA, but by disturbances in early diagnosis of this type of cancer. Epigenetics deals with epigenetic mechanisms. The epigenetic changes in DNA struc- changes in gene expression that are not determined by changes ture are the result of post-replication modification in DNA in the DNA sequence. Epigenetic changes refer to changes in and/or post-translational modification of proteins associated the structure of DNA, which are the result of DNA modifica- with DNA. In contrast to mutations, epigenetic modifica- tion after replication and/or post-translational modification tions are reversible and dynamically occur. These epigenetic of proteins associated with DNA. In contrast to mutations, mechanisms include aberrant DNA methylation (hypermeth- epigenetic changes are reversible and occur very rapidly. ylation and hypomethylation) and modifications of histones, The major epigenetic mechanisms include DNA methylation, chromatin remodeling and changes in gene expression caused modification of histone proteins, chemical modification and by non-coding RNAs (ncRNAs). Epigenetic mechanisms lead chromatin remodeling changes in gene expression caused by to genomic instability and inappropriate gene expression and microRNAs (miRNAs). Epigenetic changes play an important are the best-characterized alteration in PC. Epigenetic mecha- role in malignant transformation and can be specific to types nisms play an important role in the initiation and development of cancers including prostate cancer. of PC. Global and gene-specific hypermethylation and hypo- methylation as well as histone modifications have been found to be associated with PC (1,2). Contents 2. DNA methylation and prostate cancer 1. Introduction 2. DNA methylation and prostate cancer DNA methylation plays an important role in DNA repair, 3. Histone modifications and prostate cancer recombination and replication, as well as regulation of gene 4. Role of histone modification in the MDR1 gene silencing activity. DNA methylation involves the addition of a methyl in prostate cancer group to the 5'-carbon of cytosine in CpG dinucleotide 5. Modifications of histones and proteins polycomb and Trithorax sequences. This process is catalyzed by a family of DNA in the development of prostate cancer methyltransferases (DNMTs). CpG islands are CpG-rich areas 6. Conclusion of 200 bp to several kilobases in length, usually located near the promoters of highly expressed genes, and are the sites of common methylation in human tumors, including the prostate. CpG islands, in more than 55% of cases, form clusters and their methylation/demethylation results in the inhibition/activation of transcription. Thus, methylation of CpG islands in promoter regions of genes may prevent or deregulate the synthesis of Correspondence to: Dr Maria Nowacka-Zawisza, Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, gene products (3-5). University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland Three active DNMTs have been identified (DNMT1, E-mail: [email protected] DNMT3A and DNMT3B). A fourth enzyme previously known as DNMT2 is not a DNA methyltransferase. DNMT2 Key words: DNA methylation, epigenetics, histone modification, or TRDMT1 has strong sequence similarities with 5-meth- prostate cancer ylcytosine methyltransferases, but the enzyme was shown to methylate position 38 in aspartic acid transfer RNA and does not methylate DNA. The smallest mammalian DNMT2 2588 Nowacka-Zawisza and WIŚNIK: EPIGENETICS AND PROSTATE CANCER Figure 1. Role of DNA methylation in cancer (9). is believed to participate in the recognition of DNA damage, CD44), cell cycle control (CDKN2A), apoptosis (PYCARD) and DNA recombination and mutation repair. DNMT1, the major also are related to suppressor genes (APC, RARβ, RARRES1 enzyme responsible for maintenance of the DNA methyla- and RASSF1) (5,8,10). Specific genes implicated within each tion pattern is located at the replication fork and methylates category are summarized in Table I. newly biosynthesized DNA. DNMT3A and DNMT3B cannot The glutathione S-transferase π 1 gene (GSTP1) encodes differentiate between unmethylated and hemi-methylated CpG glutathione S-transferase belonging to the π class. It is respon- sites, and they cannot copy a specific pattern of methylation or sible for protecting cells from oxidative stress and chemical contribute to the maintenance of the methylation pattern (6). attacks. GSTP1 is involved in the metabolism, detoxification Proteins that bind to methylated CpG islands (MBP, and elimination of compounds potentially genotoxic, and methyl-CpG binding proteins) which include: MBP1, MBP2, prevents DNA damage and initiation of neoplastic transforma- MBP3 and methyl CpG-binding protein-2 (MeCP2) recognize tion. GSTP1 is one of the earliest identified genes which is methylated CpG islands in the promoter regions of the genes. hypermethylated in PC. GSTP1 hypermethylation has been These proteins at the N-terminal contain methyl-CpG-binding found in 13.3-100% of PC cases, whereas methylation of domain (MBD) and in the central portion transcriptional GSTP1 within CpG dinucleotides has not been noted in normal repression domain (TRD). MBP proteins can activate histone cells. GSTP1 hypermethylation is present at all stages of PC deacetylase (HDAC), and/or co-repressors of transcription, development, and the assessment of the methylation profile of after recognizing methylated DNA. Then, chromatin under- this gene allows the differentiation of types and subtypes of goes strong condensation, preventing access of transcription PC which may facilitate early diagnosis. GSTP1 gene meth- factors to the promoter's genes (7). ylation profile can be assessed not only in serum but also in Disturbances of DNA methylation can lead to malignant other body fluids. In 39-83.2% of PC patients, GSTP1 DNA transformation. In PC, hypermethylation and hypomethylation methylation was detected in urine (11,12). Hypermethylation of DNA can be observed. In normal cells, CpG islands are of GSTP1 DNA was detected in plasma samples from 27 of 31 protective against excessive methylation by active transcrip- (92.86%) patients with PC (13). Methylated GSTP1 DNA in tion, DNA demethylation, regulation of replication and the serum is present in 28-32% of men with metastatic PC (14,15). establishment of appropriate local chromatin structure, Mahon et al (16) identified plasma methylated GSTP1 DNA as impeding access to methyl-DNA transferase. In tumor cells, a potential prognostic marker in men with castration-resistant the mechanisms as described above are altered, resulting in PC as well as a potential surrogate therapeutic efficacy marker abnormal DNA methylation regulation (2,8). for chemotherapy. A common molecular feature associated with tumorigen- The O-6-methylguanine-DNA methyltransferase gene esis including PC is hypermethylation of cytosines 5' in CpG (MGMT) encoding enzyme removes alkyl adducts from the islands within the regulatory (promoter) region of suppressor O6 position of guanine. Methylation of the MGMT gene genes resulting in gene silencing. In contrast, hypomethylation promoter region has been detected in PC patients and cell in the promoter region of oncogenes in tumors reactivates lines (17-19). DNA hypermethylation of CpG dinucleotides transcription (Fig. 1). Moreover, 5-methyl cytosine is unstable of the MGMT gene has been associated with decrease and/or and mutates to thymine and methylated CpG sites degrade to total loss of expression of this gene, and results in the devel- TpG/CpA (9). opment of carcinoma. A study conducted by Sidhu et al (18) indicated that development of prostate carcinoma is correlated DNA hypermethylation. In PC, many CpG islands exhibit with modification of the MGMT methylation pattern. aberrant hypermethylation. Genes undergoing methylation in PC tumor cell invasion and progression have been found PC include genes involved in key cellular functions such as to be associated with E-cadherin-1 (CDH1) gene promoter DNA repair (GSTP1 and MGMT), cell adhesion (CDH1 and hypermethylation. The effect of increased methylation of ONCOLOGY REPORTS 38: 2587-2596, 2017 2589 Table I. Genes hypermethylated in prostate cancer. Chromosomal Hypermethylation in Gene location Function prostate cancer (%) Refs. GSTP1 11q13 Detoxification, DNA repair 13-100 (13,16,72-82) MGMT 10q26 Detoxification, DNA repair 0-76 (17-19,35) CDH1 16q22.1 Cell adhesion 0-72 (22,29,83) CD44 11p13 Cell-cell interactions, cell adhesion and 20-78 (21,23,84) migration CCND2 12p13 Regulation of cyclin-dependent protein 8.4-99
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