Epigenetic events in malignant melanoma

Irreversible changes in the DNA sequence, including chromosomal deletions or amplification, activating or inactivating mutations in genes, have been implicated in the development and progression of melanoma. However, increasing attention is being turned towards the participation of 'epigenetic' events in melanoma progression that do not affect DNA sequence, but which nevertheless may lead to stable inherited changes in gene expression. Epigenetic events including histone modifications and DNA methylation play a key role in normal development and are crucial to establishing the correct program of gene expression. In contrast, mistargeting of such epigenetic modifications can lead to aberrant patterns of gene expression and loss of anti-cancer checkpoints. Thus, to date at least 50 genes have been reported to be dysregulated in melanoma by aberrant DNA methylation and accumulating evidence also suggests that mistargetting of histone modifications and altered chromatin remodeling activities will play a key role in melanoma. This review gives an overview of the many different types of epigenetic modifications and their involvement in cancer and especially in melanoma development and progression.     

Histone modifications as a platform for cancer therapy

Tumorigenesis and metastasis are a progression of events resulting from alterations in the processing of the genetic information. These alterations result from stable genetic changes (mutations) involving tumor suppressor genes and oncogenes (e.g., ras, BRAF) and potentially reversible epigenetic changes, which are modifications in gene function without a change in the DNA sequence. Mutations of genes coding for proteins that directly or indirectly influence epigenetic processes will alter the cell's gene expression program. Epigenetic mechanisms often altered in cancer cells are DNA methylation and histone modifications (acetylation, methylation, phosphorylation). This article will review the potential of these reversible epigenetic processes as targets for cancer therapies.     

DNA methylation: the nuts and bolts of repression

DNA methylation is an epigenetic modification which plays an important role in chromatin organization and gene expression. DNA methylation can silence genes and repetitive elements through a process which leads to the alteration of chromatin structure. The mechanisms which target DNA methylation to specific sites in the genome are not fully understood. In this review, we will discuss the mechanisms which lead to the long-term silencing of genes and will survey the progression that has been made in determining the targeted mechanisms for de novo DNA methylation.     

Connections between epigenetic gene silencing and human disease

Alterations in epigenetic gene regulation are associated with human disease. Here, we discuss connections between DNA methylation and histone methylation, providing examples in which defects in these processes are linked with disease. Mutations in genes encoding DNA methyltransferases and proteins that bind methylated cytosine residues cause changes in gene expression and alterations in the patterns of DNA methylation. These changes are associated with cancer and congenital diseases due to defects in imprinting. Gene expression is also controlled through histone methylation. Altered levels of methyltransferases that modify lysine 27 of histone H3 (K27H3) and lysine 9 of histone H3 (K9H3) correlate with changes in Rb signaling and disruption of the cell cycle in cancer cells. The K27H3 mark recruits a Polycomb complex involved in regulating stem cell pluripotency, silencing of developmentally regulated genes, and controlling cancer progression. The K9H3 methyl mark recruits HP1, a structural protein that plays a role in heterochromatin formation, gene silencing, and viral latency. Cells exhibiting altered levels of HP1 are predicted to show a loss of silencing at genes regulating cancer progression. Gene silencing through K27H3 and K9H3 can involve histone deacetylation and DNA methylation, suggesting cross talk between epigenetic silencing systems through direct interactions among the various players. The reversible nature of these epigenetic modifications offers therapeutic possibilities for a wide spectrum of disease.     

黑色素瘤发生发展中的表观遗传学调控

人恶性黑色素瘤(malignant melanoma)是近年来高发病率和高死亡率的肿瘤之一.目前尚缺乏有效的治疗方法.而表观遗传如DNA甲基化(DNA methylation)、组蛋白修饰(histonemodification)、染色质重塑(chromatin remodeling)及RNA干扰(RNA interference,RNAi)等改变在人黑色素瘤的发生、发展和转移中有重要作用.阐明黑色素瘤发生发展的表观遗传学机制已引起了学者的普遍关注.本文综述了人类黑色素瘤发生发展中所特异的表观遗传改变:CpG岛的异常甲基化修饰、组蛋白甲基化和乙酰化修饰、染色质重塑以及microRNA在黑色素瘤发生和转移中的作用,并对应用表观遗传修饰治疗人类黑色素瘤进行了探讨.     

The methylation landscape of tumour metastasis

The metastatic cascade which leads to the death of cancer patients results from a multi‐step process of tumour progression caused by genetic and epigenetic alterations in key regulatory molecules. It is, therefore, crucial to improve our understanding of the regulation of genes controlling the metastatic process to identify predictive biomarkers and to develop more effective therapies to treat advanced disease. The study of epigenetic mechanisms of gene regulation offers a novel approach for innovative diagnosis and treatment of cancer patients. Recent discoveries provide compelling evidence that the methylation landscape (changes in both DNA methylation and histone post‐translational modifications) is profoundly altered in cancer cells and contributes to the altered expression of genes regulating tumour phenotypes. However, the impact of methylation events specifically on the advanced metastatic process is poorly understood compared with the initial oncogenic events. Moreover, the characterisation of a large number of histone‐modifying enzymes has revealed their active roles in cancer progression, via the regulation of specific target genes controlling different metastatic phenotypes. Here, we discuss two main methylating events (DNA methylation and histone‐tail methylation) involved in oncogenesis and metastasis formation. The potential reversibility of these molecular events makes them promising biomarkers of metastatic potential and potential therapeutic targets.     

Epigenetic regulation of insulin-like growth factor binding protein-3 (IGFBP-3) in cancer

Epigenetics refers to heritable changes in gene expression that are independent of alterations in DNA sequence. It is now accepted that disruption of epigenetic mechanisms plays a key role in the pathogenesis of cancer: culminating in altered gene function and malignant cellular transformation. DNA methylation and histone modifications are the most widely studied changes but non-coding RNAs such as miRNAs are also considered part of the epigenetic machinery. The insulin-like growth factor (IGF) axis is composed of two ligands, IGF-I and –II, their receptors and six high affinity IGF binding proteins (IGFBPs). The IGF axis plays a key role in cancer development and progression. As IGFBP genes have consistently been identified among the most common to be aberrantly altered in tumours, this review will focus on epigenetic regulation of IGFBP-3 in cancer for which the majority of evidence has been obtained.     

Technologies for targeting DNA methylation modifications: Basic mechanism and potential application in cancer

DNA methylation abnormalities are regarded as critical event for cancer initiation and development. Tumor-associated genes encompassing aberrant DNA methylation alterations at specific locus are correlated with chromatin remodeling and dysregulation of gene expression in various malignancies. Thus, technologies designed to manipulate DNA methylation at specific loci of genome are necessary for the functional study and therapeutic application in the context of cancer management. Traditionally, the method for DNA methylation modifications demonstrates an unspecific feature, adversely causing global-genome epigenetic alterations and confusing the function of desired gene. Novel approaches for targeted DNA methylation regulation have a great advantage of manipulating gene epigenetic alterations in a more specific and efficient method. In this review, we described different targeting DNA methylation techniques, including both their advantages and limitations. Through a comprehensive understanding of these targeting tools, we hope to open a new perspective for cancer treatment.     

Epi-drugs to fight cancer: from chemistry to cancer treatment, the road ahead

In addition to genetic events, a variety of epigenetic events have been widely reported to contribute to the onset of many diseases including cancer. DNA methylation and histone modifications (such as acetylation, methylation, sumoylation, and phosphorylation) involving chromatin remodelling are among the most studied epigenetic mechanisms for regulation of gene expression leading, when altered, to some diseases. Epigenetic therapy tries to reverse the aberrations followed to the disruption of the balance of the epigenetic signalling ways through the use of both natural compounds and synthetic molecules, active on specific epi-targets. Such epi-drugs are, for example, inhibitors of DNA methyltransferases, histone deacetylases, histone acetyltransferases, histone methyltransferases, and histone demethylases. In this review we will focus on the chemical aspects of such molecules, joined to their effective (or potential) application in cancer therapy.     

Radiation-induced epigenetic alterations after low and high LET irradiations

Epigenetics, including DNA methylation and microRNA (miRNA) expression, could be the missing link in understanding radiation-induced genomic instability (RIGI). This study tests the hypothesis that irradiation induces epigenetic aberrations, which could eventually lead to RIGI, and that the epigenetic aberrations induced by low linear energy transfer (LET) irradiation are different than those induced by high LET irradiations. GM10115 cells were irradiated with low LET X-rays and high LET iron (Fe) ions and evaluated for DNA damage, cell survival and chromosomal instability. The cells were also evaluated for specific locus methylation of nuclear factor-kappa B (NFκB), tumor suppressor in lung cancer 1 (TSLC1) and cadherin 1 (CDH1) gene promoter regions, long interspersed nuclear element 1 (LINE-1) and Alu repeat element methylation, CpG and non-CpG global methylation and miRNA expression levels. Irradiated cells showed increased micronucleus induction and cell killing immediately following exposure, but were chromosomally stable at delayed times post-irradiation. At this same delayed time, alterations in repeat element and global DNA methylation and miRNA expression were observed. Analyses of DNA methylation predominantly showed hypomethylation, however hypermethylation was also observed. We demonstrate that miRNA expression levels can be altered after X-ray irradiation and that these miRNA are involved in chromatin remodeling and DNA methylation. A higher incidence of epigenetic changes was observed after exposure to X-rays than Fe ions even though Fe ions elicited more chromosomal damage and cell killing. This distinction is apparent at miRNA analyses at which only three miRNA involved in two major pathways were altered after high LET irradiations while six miRNA involved in five major pathways were altered after low LET irradiations. This study also shows that the irradiated cells acquire epigenetic changes suggesting that epigenetic aberrations may arise in the cell without initiating chromosomal instability.     

DNA methylation in health, disease, and cancer

The spatial arrangement and three-dimensional structure of DNA in the nucleus is controlled through the interdigitation of DNA binding proteins such as histones and their modifiers, the Polycomb-Trithorax proteins, and the DNA methyltransferase enzymes. DNA methylation forms the foundation of chromatin and is crucial to epigenetic gene regulation in mammals. Disease pathogenesis mediated through infectious agents, inflammation, aging, or genetic damage often involves changes in gene expression. In particular, cellular transformation coincides with multiple changes in chromatin architecture, many of which appear to affect genome integrity and gene expression. Infectious agents, such as viruses directly affect genome structure and induce methylation of particular sequences to suppress host immune responses. Hyperproliferative tissues such as those in the gastrointestinal tract and colon have been shown to gradually acquire aberrant promoter hypermethylation. Here we review recent findings on altered DNA methylation in human disease, with particular focus on cancer and the increasingly large number of genes subject to tumor-specific promoter hypermethylation and the possible role of aberrant methylation in tumor development.     

Epigenetic regulation in human melanoma: past and future

The development and progression of melanoma have been attributed to independent or combined genetic and epigenetic events. There has been remarkable progress in understanding melanoma pathogenesis in terms of genetic alterations. However, recent studies have revealed a complex involvement of epigenetic mechanisms in the regulation of gene expression, including methylation, chromatin modification and remodeling, and the diverse activities of non-coding RNAs. The roles of gene methylation and miRNAs have been relatively well studied in melanoma, but other studies have shown that changes in chromatin status and in the differential expression of long non-coding RNAs can lead to altered regulation of key genes. Taken together, they affect the functioning of signaling pathways that influence each other, intersect, and form networks in which local perturbations disturb the activity of the whole system. Here, we focus on how epigenetic events intertwine with these pathways and contribute to the molecular pathogenesis of melanoma.     

Identification of tumor suppressors and oncogenes from genomic and epigenetic features in ovarian cancer

The identification of genetic and epigenetic alterations from primary tumor cells has become a common method to identify genes critical to the development and progression of cancer. We seek to identify those genetic and epigenetic aberrations that have the most impact on gene function within the tumor. First, we perform a bioinformatic analysis of copy number variation (CNV) and DNA methylation covering the genetic landscape of ovarian cancer tumor cells. We separately examined CNV and DNA methylation for 42 primary serous ovarian cancer samples using MOMA-ROMA assays and 379 tumor samples analyzed by The Cancer Genome Atlas. We have identified 346 genes with significant deletions or amplifications among the tumor samples. Utilizing associated gene expression data we predict 156 genes with altered copy number and correlated changes in expression. Among these genes CCNE1, POP4, UQCRB, PHF20L1 and C19orf2 were identified within both data sets. We were specifically interested in copy number variation as our base genomic property in the prediction of tumor suppressors and oncogenes in the altered ovarian tumor. We therefore identify changes in DNA methylation and expression for all amplified and deleted genes. We statistically define tumor suppressor and oncogenic features for these modalities and perform a correlation analysis with expression. We predicted 611 potential oncogenes and tumor suppressors candidates by integrating these data types. Genes with a strong correlation for methylation dependent expression changes exhibited at varying copy number aberrations include CDCA8, ATAD2, CDKN2A, RAB25, AURKA, BOP1 and EIF2C3. We provide copy number variation and DNA methylation analysis for over 11,500 individual genes covering the genetic landscape of ovarian cancer tumors. We show the extent of genomic and epigenetic alterations for known tumor suppressors and oncogenes and also use these defined features to identify potential ovarian cancer gene candidates.