23.3 Epigenetic Changes Are Often Associated with Cancer

Epigenetic changes—alterations to chromatin structure that affect gene expression (see Chapter 21)—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 cancers. For example, almost 90% of cases of follicular lymphoma exhibit mutations in the MLL2 gene, which encodes a histone methyltransferase enzyme; 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 (enzyme that removes methyl groups from histone proteins) is mutated in a number of different types of cancer.

A second line of evidence suggesting that epigenetic alterations are important in cancer comes from recent genomic studies that have compared chromatin structure of cancer cells and normal cells from the same individual. These studies often find that cancer cells have significant alterations to DNA methylation and histone structure. One type of epigenetic alteration often observed in cancer cells is an overall level of less DNA methylation (hypomethylation). As discussed in Chapter 17, 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.

A number of studies have observed that although the overall level of DNA methylation is often lower in cancer cells, some specific CpG islands (see Chapter 17) have extra methylation (are hypermethylated). For example, one study found that 5% to 10% of normally unmethylated CpG islands located at promoters become abnormally methylated in cancer cells. This excess methylation may inhibit transcription of tumor-suppressor genes, thus stimulating the development of cancer. The methylation of the promoter of the Apaf-1 gene is seen in many malignant melanoma cells. Apaf-1 helps bring about apoptosis of cells with damaged DNA; methylation of its promoter reduces the expression of Apaf-1, interrupting the process of apoptosis and allowing abnormal cancer cells to survive.

Research has also demonstrated that the histone proteins in nucleosomes, the fundamental unit 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. Global patterns of histone acetylation are often altered in cancer cells. However, acetylation not only affects histones but also a number of other proteins that may stimulate or suppress cell division, so whether the effect of acetylation on cancer occurs through changes to chromatin structure is unclear. Epigenetic processes are receiving increasing attention by cancer researchers because they may be amenable to drug therapy.