We have just seen how mutations can undermine control of cell proliferation by inactivating tumor-suppressor genes. However, these types of genes can also be silenced by repressing their expression. Changes in DNA methylation, as well as changes in the activity of histone-modifying enzymes or chromatin-remodeling complexes, are now recognized as major drivers of tumorigenesis.

As we saw in Chapter 9, DNA methylation occurs at cytosines of CpG islands, which are found largely in promoters of genes. Methylation of these Cs leads to repression of the promoters. A large fraction of colorectal cancers are characterized by DNA hypermethylation. DNA hypomethylation is also a hallmark of cancer. The promoters of many genes involved in cancer are hypomethylated, and expression of the genes under their control is therefore increased. For example, 25 percent of acute myeloid leukemias are characterized by DNA hypomethylation that is due to inactivating mutations in an enzyme that catalyzes the methylation of CpG dinucleotides. A recently discovered DNA modification related to DNA methylation involves the conversion of 5-methylcytosine at CpG islands to a hydroxylated variant (5-hydroxylmethylcytosine). This type of DNA modification has also been implicated in cancer. The enzymes that catalyze these conversions are members of the TET family of DNA hydroxylases. These enzymes require α-ketoglutarate as cofactors and are inhibited by the oncometabolite 2-hydroxyglutarate (see Figure 24-4).

Genes encoding chromatin modifiers and regulators have also emerged as drivers of tumorigenesis. Systematic whole-genome sequencing of many tumor types has revealed highly recurrent alterations in approximately 40 genes encoding epigenetic regulators. Recurrent mutations were found in genes encoding enzymes that modify histones or that interpret these post-translational modifications. Genes encoding histone methyl transferases, histone demethylases, and histone acetyl transferases have all been found mutated in a wide variety of tumors. Interestingly, tumors typically harbor only a single mutated allele of a gene encoding a chromatin-modifying enzyme, indicating that these mutations are haplo-insufficient. Presumably, losing both alleles would kill the cell, but having only one functional allele alters the expression of target genes sufficiently to promote tumorigenesis.

Central among the chromatin-remodeling factors implicated in cancer are the SWI/SNF complexes. These large and diverse multiprotein complexes, which have an ATP-dependent helicase at their core, often control histone modification and chromatin remodeling (see Chapter 9). For example, they can cause changes in the positions or structures of nucleosomes, making genes accessible or inaccessible to DNA-binding proteins that control transcription. If a target gene is normally activated or repressed by SWI/SNF-mediated chromatin changes, mutations in the genes encoding SWI or SNF proteins will cause changes in the expression of that gene. Studies with transgenic mice suggest that SWI/SNF plays a role in repressing the expression of E2F genes, thereby inhibiting progression through the cell cycle. Thus loss of SWI/SNF function, just like loss of Rb function, can lead to overgrowth and perhaps cancer. Indeed, in mice, the Rb protein recruits SWI/SNF proteins to repress transcription of the genes encoding E2Fs.

Recent evidence from humans and mice has strongly implicated the SNF5 gene in cancer. The SNF5 protein is a core member of the SWI/SNF complex. In humans, inactivating somatic SNF5 mutations cause rhabdoid tumors, which most commonly form in the kidney, and an inherited (familial) disposition to form brain and other tumors. Subsequent studies have found genes encoding various BAF proteins, which are also subunits of the SWI/SNF complex, to be mutated in 40 percent of renal cancers, 50 percent of ovarian cancers, and a high fraction of liver and bladder cancers. In summary, epigenetic misregulation has emerged as a major contributor to tumorigenesis. In hindsight, this notion is probably not surprising, given that epigenetic regulation offers the opportunity to change the expression of many factors and regulatory pathways simultaneously.