Epigenetic Changes Associated with Cancer

Epigenetic changes—alterations to chromatin structure that affect gene expression (see Chapter 12)—are seen in many cancer cells. Two broad lines of evidence suggest that epigenetic changes play an important role in cancer progression. First, genes encoding proteins that are important regulators of epigenetic changes are often mutated in some types of cancer. For example, almost 90% of cases of follicular lymphoma exhibit mutations in the MLL2 gene, which encodes a histone methyltransferase; this enzyme adds methyl groups to DNA, a type of epigenetic modification that alters chromatin structure and affects transcription. Similarly, the UTX gene, which encodes a histone demethylase (an enzyme that removes methyl groups from DNA), is mutated in a number of different types of cancer.

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A second line of evidence suggesting that epigenetic alterations are important in cancer comes from recent genomic studies that have compared the chromatin structure of cancer cells with that of normal cells from the same individual. These studies often find that the cancer cells have significant alterations to DNA methylation patterns and histone structure.

One type of epigenetic alteration often observed in cancer cells is an overall lower level of DNA methylation (hypomethylation). As discussed in Chapter 12, DNA methylation is often associated with repression of transcription. It is assumed that hypomethylation leads to transcription of oncogenes, which then stimulate cancer. Some evidence also suggests that hypomethylation causes chromosome instability, a hallmark of many tumors. Tumor cells from mice that have been genetically engineered to have reduced DNA methylation show increased gains and losses of chromosomes, but how hypomethylation might cause chromosome instability is unclear.

Research has also demonstrated that the histone proteins in nucleosomes, the fundamental units of chromatin, are often abnormally modified in cancer cells. Modification of histone proteins, including methylation and acetylation, alters chromatin structure and affects whether transcription occurs (see Chapter 12). Genome-wide patterns of histone acetylation are often altered in cancer cells. Epigenetic processes are receiving increasing attention from cancer researchers because they may be amenable to drug therapy.

CONCEPTS

Epigenetic changes, including DNA methylation and histone modification, are often associated with cancer.