MYC—Master Regulator of the Cancer Epigenome and Transcriptome

MYC—Master Regulator of the Cancer Epigenome and Transcriptome

G C A T T A C G G C A T genes Review MYC—Master Regulator of the Cancer Epigenome and Transcriptome Candace J. Poole and Jan van Riggelen * Augusta University, Department of Biochemistry and Molecular Biology, 1410 Laney-Walker Blvd., Augusta, GA 30912, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-706-721-0856; Fax: +1-706-721-6608 Academic Editor: Frank Buchholz Received: 28 February 2017; Accepted: 10 May 2017; Published: 13 May 2017 Abstract: Overexpression of MYC is a hallmark of many human cancers. The MYC oncogene has long been thought to execute its neoplastic functions by acting as a classic transcription factor, deregulating the expression of a large number of specific target genes. However, MYC’s influence on many of these target genes is rather modest and there is little overlap between MYC regulated genes in different cell types, leaving many mechanistic questions unanswered. Recent advances in the field challenge the dogma further, revealing a role for MYC that extends beyond the traditional concept of a sequence-specific transcription factor. In this article, we review MYC’s function as a regulator of the cancer epigenome and transcriptome. We outline our current understanding of how MYC regulates chromatin structure in both a site-specific and genome-wide fashion, and highlight the implications for therapeutic strategies for cancers with high MYC expression. Keywords: MYC; chromatin remodeling; cancer 1. Introduction The importance of MYC in human development and disease has generated intense research interest over the past 30 years, resulting in numerous original articles and reviews (for example, see [1–3]). The MYC family is comprised of c-MYC (herein referred to as MYC, unless otherwise specified), N-MYC, and L-MYC, which encode for basic helix–loop–helix leucine zipper (bHLH-Zip) transcription factors [4] that have been found to play a unique role in regulating an extensive range of biological processes including stemness, cellular proliferation, and neoplastic transformation. While the activity of MYC family members is tightly regulated in non-malignant cells, their constitutive expression is directly linked to the pathogenesis of a wide variety of human cancers [5–8]. The fact that elevated levels of MYC proteins are found in 60–70% of all cancers (reviewed in [1]) and the discovery that tumors can be dependent on continuous MYC expression (known as oncogene addiction) [9] have made this family of oncogenes a highly promising therapeutic target. However, even after three decades of research, both the exact molecular mechanism of how MYC promotes tumorigenesis and a pharmacologic inhibitor selectively targeting the oncogene remain elusive. MYC exerts its neoplastic features by increasing autonomous cellular proliferation, growth, angiogenesis, and genomic destabilization while blocking differentiation (see Figure1) (reviewed in [10]). However, these diverse cellular functions are attributed to the still not completely understood ability of MYC to control the expression of a large set of genes. MYC proteins have first been described as sequence-specific transcription factors, forming heterodimeric complexes with MYC-Associated Factor X (MAX). MYC–MAX complexes are now known to recognize a consensus sequence known as Enhancer box (“E-box”), activating the transcription of genes [11–13]. This finding sparked a comprehensive search for MYC target genes and their function and involvement in neoplastic transformation [14]. However, the scope and complexity of MYC’s action became apparent when Genes 2017, 8, 142; doi:10.3390/genes8050142 www.mdpi.com/journal/genes Genes 2017, 8, 142 2 of 28 Genes 2017, 8, 142 2 of 28 neoplastic transformation [14]. However, the scope and complexity of MYC’s action became apparent whenit was it discovered was discovered that there that arethere approximately are approximately 20,000 20,000 E-box sitesE-box in sites the humanin the human genome, genome, of which of whichonly a only subset a issubset differentially is differentially bound bybound MYC by in MYC a cell in type-specific a cell type- fashionspecific [fashion15]. To further[15]. To increase further increasethe complexity, the complexity, MYC was MYC also was later also found later to found be capable to be capable of repressing of repressing the transcription the transcription of genes of genesthrough through interactions interactions with other with transcription other transcription factors [16factors–18]. It[16 turned–18]. It out turned thatboth out MYC’sthat both activating MYC’s activatingand repressing and repressing functions arefunctions critical are for critical tumorigenesis for tumorigenesis and depend and on depend the recruitment on the recruitment of chromatin of chromatinmodifying modifying co-factors thatco-factors remodel that chromatin remodel chromatin structurein structure the vicinity in the of vicinity the binding of the sites. binding However, sites. However,MYC acts ratherMYC acts weakly rather at manyweakly of itsat many target of gene its promoters,target gene andpromoters, even genomic and even location genomic profiles location have profilesoften proven have non-predictive often proven ofnon MYC-dependent-predictive of transcriptionalMYC-dependent regulation transcriptional [15]. Furthermore, regulation despite [15]. Fconsiderableurthermore, effortsdespite to considerable identify a MYC efforts target to identify gene signature a MYC target using gene comparative signature geneusing profilingcomparative and genegenomic profiling location and analyses, genomic little location overlap analyses, between MYClittle regulatedoverlap genesbetween in differentMYC regulated cell types genes has been in differentfound [14 cell,19]. types To explain has been these found discrepancies, [14,19]. To the explain classic mechanistic these discrepancies, model has the recently classic been mechanistic extended modelto incorporate has recently MYC’s been function extended as a to regulator incorporate of global MYC’s chromatin function structureas a regulator and transcription.of global chromatin In this structurearticle, we and review transcription. the role of In MYC this article, as a regulator we review of the the cancer role of epigenome MYC as a andregulator transcriptome of the cancer both epigenomethrough site-specific, and transcr localiptome mechanisms both through as well site as-specific, genome-wide local mechanisms effects, and highlight as well as the genome potential-wide for effectsnovel therapeutic, and highlight strategies. the potential for novel therapeutic strategies. Figure 1. 1. MYCMYC as asa transcription a transcription factor factor and andoncogene. oncogene. Display Display of the X of-ray the crystal X-ray structure crystal structure of a MYC of– MAXa MYC–MAX heterodimer heterodimer bound boundto DNA to DNAas a assite a site-specific-specific transcription transcription factor factor complex complex [20,21] [20,21].. Overexpression of MYC causes the deregulation of central cellular processes including cell cycle progression, metabolism, differentiation, differentiation, and and angiogenesis angiogenesis,, together together contributi contributingng to neoplastic transformation.transformation. Deregulated Deregulated MYC MYC expression expression is is implicated implicated in in a a wide wide variety variety of of human human cancer cancer types types includingincluding Burkitt’sBurkitt’s lymphoma, lymphoma, acute acute lymphoblastic lymphoblastic leukemia leukemia (ALL), (ALL) and, neuroblastoma. and neuroblastoma. Image createdImage createdwith: UCSF with: Chimera; UCSF Chimera; PDB: 1NKP. PDB: 1NKP. 2. Recruitme Recruitmentnt of Chromatin Modifiers Modifiers for MYC-DependentMYC-Dependent Transactivation The gene gene-specific-specific transactivation model model depends depends on on the ability of MYC MYC–MAX–MAX complexes to recruit chromatin chromatin-modifying-modifying co co-factors.-factors. These These change change the the chromatin chromatin structure structure in the in thevicinity vicinity of the of bindingthe binding site, site,allowing allowing or preventing or preventing the thetranscription transcription of the of thecorresponding corresponding gene gene by regulating by regulating its accessibilityits accessibility to the to basal the basal transcriptional transcriptional machinery machinery or releasing or releasing preloaded preloaded RNA Polymerase RNA Polymerase II (RNA II Pol(RNA II) Polfrom II) pausing. from pausing. An increasing number of chromatin modifying co co-factors-factors including chromatin chromatin “writers “writers”,,” “readers”,“readers,” andand “erasers” “erasers” have have been been found found to interact to interact directly directly or indirectly or indirectly with MYC–MAX with MYC complexes–MAX complexes(for an overview, (for an seeoverview, Figure 2see). ManyFigure of 2). these Many protein–protein of these protein interactions–protein interactions are facilitated are facilitated through throughMYC’s N-terminus, MYC’s N-terminu which harborss, which the harbors transcriptional the transcriptional activation activation domain (TAD) domain and (TAD) highly and conserved highly conservedsequence elements, sequence known elements, as “MYC known box” as (MB)“MYC 0, box” I, and (MB) II, followed 0, I, and by II, MB followed III and IV by in MB the III central and IV MYC in thedomain central ([22 MYC] and domain reviewed ([22 in] [and23]). reviewed MB I, II, andin [23 III]). are MB essential I, II, and for III all are

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