Academic journal article Alcohol Research: Current Reviews

Alcohol, DNA Methylation, and Cancer

Academic journal article Alcohol Research: Current Reviews

Alcohol, DNA Methylation, and Cancer

Article excerpt

According to the World Health Organization (WHO) Global Burden of Disease Project, alcohol accounts for approximately 3.2 percent of all deaths per year worldwide (corresponding to 1.8 million people) and is causally related to more than 60 different medical conditions (Rehm et al. 2004). Cancer formation (i.e., carcinogenesis) is one of the most significant consequences attributed to alcohol consumption, and approximately 3.6 percent of all cancer-related cases (5.2 percent in men and 1.7 percent in women) worldwide, as well as 3.5 percent of all cancer-related deaths are related to chronic alcohol drinking (Boffetta et al. 2006). Based on available epidemiological data, an international group of epidemiologists and alcohol researchers concluded that alcohol induces carcinogenesis in numerous organs, including the upper aerodigestive tract, liver, colorectum, and female breast (Baan et al. 2007).

Several pathogenic mechanisms contribute to alcohol-induced carcinogenesis in each type of cancer. The most commonly cited mechanisms include the effect of acetaldehyde--the first metabolite of ethanol oxidation--and oxidative stress (Seitz and Stickel 2007). Increasing evidence shows that alcohol also can induce epigenetic alterations, for example, in pathological conditions such as fetal alcohol spectrum disorders (Kobor and Weinberg 2011). Epigenetic alterations also are a hallmark of cancer development in general (Esteller 2008). Therefore, this article reviews the available evidence that such changes also could be an important contributory factor to alcohol-induced carcinogenesis. In particular, it discusses the role of DNA methylation in carcinogenesis and how alcohol may affect the pathways that regulate the availability of S-adenosylmethionine (SAMe), the principal biological methyl donor for methylation reactions. (For a list of abbreviations of the names for genes, proteins, and other compounds as well as their functions, see table).

DNA Methylation and Cancer

DNA methylation plays a critical role in the control of gene activity. This methylation almost exclusively involves the addition of a methyl group to carbon 5 of cytosine nucleotides, and specifically those cytosines that precede guanines (i.e., are part of CpG dinucleotides). CpG dinucleotides tend to cluster either in regions called CpG islands, which are located in approximately 60 percent of human gene promoters, or in regions that contain large repetitive DNA sequences (e.g., centromeres and retrotransposons). In the former case, the CpG dinucleotides generally tend to remain unmethylated, whereas in the latter case they mostly are methylated to prevent chromosome instability (Rodriguez-Paredes and Esteller 2011) (figure 1). DNA methylation also occurs in CpG island shores--that is, regions of lower CpG density that are located close to CpG islands (i.e., within 2 kb). In these three cases, DNA methylation typically is associated with repression of gene expression (i.e., transcription). In a few cases, however, DNA methylation also can enable gene transcription, namely when the methylation occurs in the body (i.e., coding sequences) of the gene rather than the promoter (Portela and Esteller 2010).

DNA methylation is mediated (i.e., catalyzed) by three main enzymes called DNA methyltransferases (DNMTs), all of which transfer a methyl group from SAMe to DNA:

* DNMT1, which also is referred to as the maintenance DNMT, completes the methylation of the par tially methylated (i.e., hemimethylated) DNA that is present in the cell after cell division and the accompanying DNA replication.

* DNMT 3A and DNMT 3B are referred to as de novo methyltransferases because they target unmethylated CpGs.

Aberrant epigenetic regulation, including altered DNA methylation, characterizes a wide range of diseases, including cancer (Portela and Esteller 2010). Compared with normal cells, the epigenome of cancer cells shows profound changes in DNA methylation patterns as well as histone modifications patterns (Rodriguez-Paredes and Esteller 2011), including the following:

* Genome-wide hypomethylation (about 20 to 60 percent less overall 5-methyl-cytosine compared with normal cells); global loss of DNA methylation occurs at many genomic regions, such as repetitive elements and retrotranposons, resulting in chromosomal instability, and activation of transposable elements and endoparasitic sequences (e. …

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