Chromatin signatures of cancer

Abstract

Changes in the pattern of gene expression play an important role in allowing cancer cells to acquire their hallmark characteristics, while genomic instability enables cells to acquire genetic alterations that promote oncogenesis. Chromatin plays central roles in both transcriptional regulation and the maintenance of genomic stability. Studies by cancer genome consortiums have identified frequent mutations in genes encoding chromatin regulatory factors and histone proteins in human cancer, implicating them as major mediators in the pathogenesis of both hematological malignancies and solid tumors. Here, we review recent advances in our understanding of the role of chromatin in cancer, focusing on transcriptional regulatory complexes, enhancer-associated factors, histone point mutations, and alterations in heterochromatin-interacting factors.

Keywords: cancer; chromatin; histone proteins.

Figure 1.

Chromatin proteins mutated in cancer. A summary of cancer mutations that affect post-translational modifications of the histone H3 N-terminal tail. Protein classes are indicated by the fill color for the ovals ([red] methyltransferase; [green] demethylase; [orange] deacetylase; [blue] histone), whereas mutational status is indicated by the outline color ([gray] loss of function; [purple] overexpressed/hyperactive). Dashed lines indicate the residue of histone H3 that is expected to be modified due to the indicated cancer mutations.

Figure 2.

Drugging the histone H3K27 methyl/acetyl switch in cancer. (A) Antagonism between H3K27 methylation and acetylation machinery. H3K27 methylation and acetylation are mutually exclusive, and the PRC2 and CBP/p300 complexes act in opposition to one another. In addition, deacetylation of H3K27ac by the HDAC1/2–NURD complex promotes PRC2-mediated repression, whereas demethylation of H3K27me3 by UTX within COMPASS or JMJD3 is required for acetylation to occur. (B) In NOTCH-driven T-ALL, the histone H3K27 demethylases UTX and JMJD3 have distinct functions. UTX acts as a tumor suppressor by activating genes such as FBXW7 that negatively regulate the NOTCH pathway. In contrast, JMJD3 exists in a complex with NOTCH and is responsible for activation of oncogenic NOTCH targets. Inhibition of JMJD3 with the small molecule GSK-J4 promotes PRC2-mediated H3K27me3 at NOTCH target genes, resulting in their silencing. (C) MPNSTs often carry mutations in the genes encoding the components of both the RAS pathway inhibitor NF1 and the PRC2 component SUZ12. In this cell type, PRC2 functions to suppress RAS target genes. Reduced H3K27 methylation by PRC2 results in increased H3K27ac, increased recruitment of BRD4, and amplification of the RAS transcriptional signature. Inhibition of BRD4 with JQ1 in combination with dampening of the RAS pathway with the MEK inhibitor PD-0325901 suppresses RAS targets, resulting in tumor regression.

Figure 3.

Maintenance of genome stability through the heterochromatin pathway. Centromeric heterochromain is essential for normal segregation of chromosomes during mitosis, and defects in this pathway result in aneuploidy. H3K9me3 and binding of HP-1 are hallmarks of heterochromatin. At pericentromeric heterochromatin, SETDB1 monomethylates H3K9, whereas Suv39 converts H3K9me1 to H3K8me2/3. Disruption of Suv39 function results in aneuploidy and lymphoma development in mice. Active deacetylation is also important for centromeric heterochromatin. Treatment of cells with the class I and II histone deacetylase inhibitor TSA results in abnormal mitosis. Similarly, Suv39 and SETDB1 are essential for telomeric heterochromatin. At telomeres, disruption of Suv39 results in loss of H3K9me2/3 and a depletion of HP-1 recruitment. However, Suv39 mutant telomeres contain increased H3K9me1 mediated by SETDB1 and exhibit abnormal telomere lengthening. Overexpression of SETDB1 has been reported in some cancers. Whereas centromeres depend on type I and II HDACs, the sirtuin deacetylase SIRT6 is essential at telomeres. Lack of SIRT6 in mice results in telomere fusions and premature senescence. In other contexts, SIRT6 functions as a tumor suppressor.