Published OnlineFirst January 6, 2017; DOI: 10.1158/0008-5472.CAN-16-2301 Cancer Review Research Mutated Chromatin Regulatory Factors as Tumor Drivers in Cancer Carl Koschmann1,2, Felipe J. Nunez2,3, Flor Mendez3, Jacqueline A. Brosnan-Cashman4, Alan K. Meeker4,5, Pedro R. Lowenstein2,3, and Maria G. Castro2,3 Abstract Genes encoding proteins that regulate chromatin structure and DNA alterations in CRFs and how these influence tumor DNA modifications [i.e., chromatin regulatory factors (CRF)] and chromatinstructureandfunction,whichinturnleadsto genes encoding histone proteins harbor recurrent mutations in tumorigenesis. We also discuss the clinical implications and most human cancers. These mutations lead to modifications in review concepts of targeted treatments for these mutations. tumor chromatin and DNA structure and an altered epigenetic Continued research on CRF mutations will be critical for our state that contribute to tumorigenesis. Mutated CRFs have now future understanding of cancer biology and the development been identified in most types of cancer and are increasingly and implementation of novel cancer therapies. Cancer Res; 77(2); regarded as novel therapeutic targets. In this review, we discuss 1–7. Ó2017 AACR. Introduction chromatin, the affinity of the DNA for the histones, and the chemical modification of histone tails and DNA (4). As an In recent years, there has been an increased interest in the example, methyl and acetyl groups can be added to and removed impact of epigenetics on tumor biology. Epigenetic modifications from specific residues of the histone 3 amino-terminal tail (e.g., can alter tumor gene expression independently of alterations in H3K27me3 denotes three methyl groups added to the 27th lysine the tumor DNA sequence. Changes in DNA methylation, histone residue). The DNA can be modified as well; methylation of a modifications, and nucleosome composition or placement play a cytosine within a CpG dinucleotide causes transcriptional silenc- critical role in tumor biology and progression. These epigenetic ing or activation, depending on the proximity to the gene (4, 6–9). changes can be driven by environmental changes and factors in The regulation of chromatin structure is tightly controlled by the tumor cells' microenvironment (1). As we have continued to CRFs, which ultimately maintain genome integrity and patterns build our understanding of epigenetic pathways in cancer, we of gene expression. There are three broad categories of chro- have circled back to the tumor DNA itself. Genes that encode matin-regulating proteins, which we will discuss herein: (i) proteins that regulate chromatin structure and DNA modifica- ATP-dependent chromatin remodeling complexes, which tions [i.e., chromatin regulatory factors (CRF)] and genes encod- insert, remove, and move nucleosomes along the DNA; (ii) ing histone proteins themselves harbor recurrent mutations in histone tail modifiers, which posttranslationally modify his- human cancers. These mutations lead to modifications in tumor tone tails by inserting or removing methyl, acetyl, and other chromatin and DNA structure, leading, in turn, to an altered groups; and (iii) DNA methyltransferase/demethylases, which epigenetic state and expression program that contribute to tumor- can alter DNA methylation (Fig. 1; refs. 3, 4). igenesis (2–5). These mutated CRFs have now been identified in Not surprisingly, proteins that are so centrally involved in most types of cancer and are increasingly regarded as novel targets patterns of gene expression can dramatically disrupt cellular for cancer treatment (2–5). behavior when mutated. Protein-altering changes in genes encod- Gene expression in eukaryotes is regulated by several mechan- ing CRFs (including point mutations, amplifications, deletions, isms, which include the placement of the nucleosome on the and fusions) are capable of locking cancer cells in an abnormal epigenetic state that promotes perpetual self-renewal without differentiation (4, 6, 8, 10). Certain CRF-altering mutations 1Department of Pediatrics, Division of Pediatric Hematology-Oncology, Univer- 2 behave as driver mutations in many human malignancies, some- sity of Michigan Medical School, Ann Arbor, Michigan. Department of Neuro- – surgery, University of Michigan Medical School, Ann Arbor, Michigan. 3Depart- times as the only driving tumor mutation (3 5). In addition, ment of Cell and Developmental Biology, University of Michigan Medical School, enzymes that generate metabolites used by CRFs can be mutated, Ann Arbor, Michigan. 4Department of Pathology, Johns Hopkins University, which can contribute to cancer development. As an example, Baltimore, Maryland. 5Department of Urology, Johns Hopkins University, Balti- multiple human cancers harbor a gain-of-function point muta- more, Michigan. tion in the active site of isocitrate dehydrogenase 1 (IDH1), Corresponding Author: Maria G. Castro, University of Michigan School of resulting in production of the metabolite 2-hydroxyglutarate Medicine, 1150 W. Medical Center Drive, MSRB II, Room 4570, Ann Arbor, MI rather than a-ketoglutarate (Fig. 1). This blocks a-ketogluta- 48109-5689. Phone: 734-764-7052; Fax: 734-764-7051; E-mail: rate–dependent demethylases, increases H3K9 and H3K27 meth- [email protected] ylation and DNA hypermethylation, and blocks tumor cell dif- doi: 10.1158/0008-5472.CAN-16-2301 ferentiation (11). In addition, recurrent gain-of-function point Ó2017 American Association for Cancer Research. mutations in histone variants HIST1H3A (H3.1) and H3F3A www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst January 6, 2017; DOI: 10.1158/0008-5472.CAN-16-2301 Koschmann et al. Enzyme that generates Histone tail modifier metabolite inhibiting CRF (e.g. MLL1, EZH2, NSD2) (e.g. mutant IDH1 -> 2HG) DNA methyl- DNA transferases demethylase (e.g. DNMT3A) (e.g. TET2) K27 K36 K79 Histone tail methylation Mutated CRF DNA methylation ATP-dependent chromatin Transcription remodeling complex Histone methytransferase/ Demethylase DNA methytransferase/ Demethylase ATP-dependent chromatin remodeling Enzyme that generates complexes metabolite inhibiting CRF (e.g. SWI/SNF) Protein-altering change in Alteration of: tumor DNA (point • DNA methylation Epigenetic state with altered mutation, amplification, • Histone tail methylation expression program deletion, fusion) of a or acetylation (e.g. perpetual tumor cell self- chromatin remodeling • Nucleosome composition renewal without differentiation) factor (CRF) or placement © 2017 American Association for Cancer Research Figure 1. Schematic demonstrates how alterations in the coding DNA of CRFs result 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 the tumor DNA. The main classes of chromatin remodeling factors are (i) ATP-dependent chromatin remodeling complexes (red triangles), which can insert, remove, and move nucleosomes along DNA; (ii) histone tail modifiers (green and red boxes), which can modify histone tails to insert or remove methyl and acetyl groups; and (iii) DNA methyltransferase/ demethylases (green and red circles), which can alter cytosine methylation on DNA. In addition, enzymes can generate metabolites (orange diamonds) that block the activity of other CRFs, such as 2-hydroxyglutarate production blocking TET2 activity in IDH1-mutated 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). (H3.3) result in critical downstream epigenetic alterations, con- alterations in nine genes have been found to impact H3K27me3 tributing to tumor growth in pediatric glioblastoma, chondro- levels, all of which are mutually exclusive (10). Recent research blastoma, and undifferentiated sarcoma (12, 13). A murine has gained significant insight into the role of CRFs' mutations in model of one of these mutations, H3 lysine 36 to methionine tumorigenesis. (H3K36M) mutation, resulted in the inhibition of H3K36 methyl- transferases, a mesenchymal differentiation block, and the gen- ATP-Dependent Chromatin Remodeling eration of murine undifferentiated sarcomas (13). A recent analysis of data from sequencing studies noted fre- Complexes quent mutations of chromatin remodeling components in 36 ATP-dependent chromatin remodeling complexes are highly cancer types (7). In a survey of multiple human cancers, the conserved from yeast to humans (14). They utilize an ATPase proportion found to have mutations in CRFs varied by tumor subunit to mobilize nucleosomes along DNA, removing histones type, with some subtypes harboring a CRF mutation in nearly all from nucleosomes, and replacing histones with other histone cases examined (3). Although mutations in CRFs as a group are variants, all of which can result in dramatic effects on transcrip- seen fairly frequently, mutations at any individual gene may be tional activity (5, 14). There are four classes of chromatin remo- found only rarely. As an example, at least 12 individual DNA deling ATPase complexes, all of which have similar ATPase OF2 Cancer Res; 77(2) January 15, 2017 Cancer Research Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2017 American