Mutated Chromatin Regulatory Factors as Tumor Drivers in Cancer

Abstract

Genes encoding proteins that regulate chromatin structure and DNA modifications [i.e., chromatin regulatory factors (CRF)] and genes encoding histone proteins harbor recurrent mutations in most human cancers. These mutations lead to modifications in tumor chromatin and DNA structure and an altered epigenetic state that contribute to tumorigenesis. Mutated CRFs have now been identified in most types of cancer and are increasingly regarded as novel therapeutic targets. In this review, we discuss DNA alterations in CRFs and how these influence tumor chromatin structure and function, which in turn leads to tumorigenesis. We also discuss the clinical implications and review concepts of targeted treatments for these mutations. Continued research on CRF mutations will be critical for our future understanding of cancer biology and the development and implementation of novel cancer therapies. Cancer Res; 77(2); 227-33. ©2017 AACR.

Figure 1. Schematic demonstrates how alterations in the coding DNA of chromatin remodeling factors (CRFs) results in tumor cell proliferation

Protein-altering changes in tumor DNA (e.g., point mutation, amplification, deletion, fusion) of a CRF can lead to downstream epigenetic changes elsewhere on tumor DNA. The main classes of chromatin remodeling factors are: (A) ATP-dependent chromatin remodeling complexes (red triangles), which can insert, remove, and move nucleosomes along DNA; (B) histone tail modifiers (green and red boxes), which can modify histone tails to insert or remove methyl and acetyl groups; and (C) DNA methyltransferase/demethylases (green and red circles), which can alter cytosine methylation on DNA. Additionally, enzymes that generate metabolites that block activity of other CRFs (orange diamonds), such as 2-hydroxyglutarate production blocking TET2 activity in IDH1-muated tumors. Mutations in CRFs lead to alterations in DNA methylation or histone tail methylation/acetylation in tumor cells or tumor precursor cells. This can result in an epigenetic state with an altered expression program (e.g., perpetual tumor cell self-renewal without differentiation). [Nucleosome image from: Stryer, Lubert (1995). Biochemistry (fourth ed.). New York - Basingstoke: W. H. Freeman and Company.]