Vulnerabilities of Mutant SWI/SNF Complexes in Cancer
2014; Cell Press; Volume: 26; Issue: 3 Linguagem: Inglês
10.1016/j.ccr.2014.07.018
ISSN1878-3686
AutoresKatherine Helming, Xiaofeng Wang, Charles W.M. Roberts,
Tópico(s)Phagocytosis and Immune Regulation
ResumoCancer genome sequencing efforts have revealed the novel theme that chromatin modifiers are frequently mutated across a wide spectrum of cancers. Mutations in genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are particularly prevalent, occurring in 20% of all human cancers. As these are typically loss-of-function mutations and not directly therapeutically targetable, central goals have been to elucidate mechanism and identify vulnerabilities created by these mutations. Here, we discuss emerging data that these mutations lead to the formation of aberrant residual SWI/SNF complexes that constitute a specific vulnerability and discuss the potential for exploiting these dependencies in SWI/SNF mutant cancers. Cancer genome sequencing efforts have revealed the novel theme that chromatin modifiers are frequently mutated across a wide spectrum of cancers. Mutations in genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are particularly prevalent, occurring in 20% of all human cancers. As these are typically loss-of-function mutations and not directly therapeutically targetable, central goals have been to elucidate mechanism and identify vulnerabilities created by these mutations. Here, we discuss emerging data that these mutations lead to the formation of aberrant residual SWI/SNF complexes that constitute a specific vulnerability and discuss the potential for exploiting these dependencies in SWI/SNF mutant cancers. SWI/SNF complexes are evolutionarily conserved multisubunit complexes that utilize the energy of ATP hydrolysis to mobilize nucleosomes and remodel chromatin (Kassabov et al., 2003Kassabov S.R. Zhang B. Persinger J. Bartholomew B. SWI/SNF unwraps, slides, and rewraps the nucleosome.Mol. 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With respect to a role in the control of gene expression, SWI/SNF complexes have been shown to serve roles in the transcriptional regulation of lineage specification and development in numerous model systems. For example, SWI/SNF complexes contribute to the development of T cells (Chi et al., 2002Chi T.H. Wan M. Zhao K. Taniuchi I. Chen L. Littman D.R. Crabtree G.R. Reciprocal regulation of CD4/CD8 expression by SWI/SNF-like BAF complexes.Nature. 2002; 418: 195-199Crossref PubMed Scopus (183) Google Scholar, Wang et al., 2011bWang X. Werneck M.B.F. Wilson B.G. Kim H.-J. Kluk M.J. Thom C.S. Wischhusen J.W. Evans J.A. Jesneck J.L. Nguyen P. et al.TCR-dependent transformation of mature memory phenotype T cells in mice.J. Clin. Invest. 2011; 121: 3834-3845Crossref PubMed Scopus (0) Google Scholar), hepatocytes (Gresh et al., 2005Gresh L. Bourachot B. Reimann A. Guigas B. Fiette L. Garbay S. Muchardt C. Hue L. Pontoglio M. Yaniv M. Klochendler-Yeivin A. The SWI/SNF chromatin-remodeling complex subunit SNF5 is essential for hepatocyte differentiation.EMBO J. 2005; 24: 3313-3324Crossref PubMed Scopus (0) Google Scholar), oligodendrocytes (Yu et al., 2013Yu Y. Chen Y. Kim B. Wang H. Zhao C. He X. Liu L. Liu W. Wu L.M.N. Mao M. et al.Olig2 targets chromatin remodelers to enhancers to initiate oligodendrocyte differentiation.Cell. 2013; 152: 248-261Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar), and embryonic stem cell self-renewal and pluripotency (Gao et al., 2008Gao X. Tate P. Hu P. Tjian R. Skarnes W.C. Wang Z. ES cell pluripotency and germ-layer formation require the SWI/SNF chromatin remodeling component BAF250a.Proc. Natl. Acad. Sci. USA. 2008; 105: 6656-6661Crossref PubMed Scopus (169) Google Scholar, Ho et al., 2009Ho L. Jothi R. Ronan J.L. Cui K. Zhao K. Crabtree G.R. An embryonic stem cell chromatin remodeling complex, esBAF, is an essential component of the core pluripotency transcriptional network.Proc. Natl. Acad. Sci. USA. 2009; 106: 5187-5191Crossref PubMed Scopus (231) Google Scholar). Specificity of SWI/SNF complexes in the control of these developmental programs is achieved in part through restricted expression and combinatorial assembly of variant SWI/SNF subunits. The SMARCD3 (BAF60C) subunit is expressed specifically in the embryonic heart, where it is essential for the control of cardiac development (Lickert et al., 2004Lickert H. Takeuchi J.K. Von Both I. Walls J.R. McAuliffe F. Adamson S.L. Henkelman R.M. Wrana J.L. Rossant J. Bruneau B.G. Baf60c is essential for function of BAF chromatin remodelling complexes in heart development.Nature. 2004; 432: 107-112Crossref PubMed Scopus (307) Google Scholar). 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Kingston R.E. Jones K.A. Emerson B.M. Functional selectivity of recombinant mammalian SWI/SNF subunits.Genes Dev. 2000; 14: 2441-2451Crossref PubMed Scopus (0) Google Scholar) and facilitates differential activation of transcriptional pathways. Ultimately, via combinatorial inclusion of variant subunits, several hundred versions of SWI/SNF complexes may exist (Wu et al., 2009Wu J.I. Lessard J. Crabtree G.R. Understanding the words of chromatin regulation.Cell. 2009; 136: 200-206Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar) and serve instructive roles in the control of fate specification. The first clue linking SWI/SNF complexes to cancer came in the late 1990s, when mutations of the gene encoding the SMARCB1 (SNF5/INI1/BAF47) subunit were identified in rhabdoid tumors (RTs), a rare but highly aggressive type of cancer that strikes young children (Biegel et al., 1999Biegel J.A. Zhou J.Y. Rorke L.B. Stenstrom C. Wainwright L.M. Fogelgren B. 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At least nine genes encoding subunits of SWI/SNF complexes have been identified as recurrently mutated in cancers derived from nearly every tissue in the body, collectively occurring in 20% of all human cancers (Figure 1) (Kadoch et al., 2013Kadoch C. Hargreaves D.C. Hodges C. Elias L. Ho L. Ranish J. Crabtree G.R. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy.Nat. Genet. 2013; 45: 592-601Crossref PubMed Scopus (269) Google Scholar, Shain and Pollack, 2013Shain A.H. Pollack J.R. The spectrum of SWI/SNF mutations, ubiquitous in human cancers.PLoS ONE. 2013; 8: e55119Crossref PubMed Scopus (155) Google Scholar). For example, inactivating mutations of ARID1A are prevalent in a wide variety of cancers, including 45% of ovarian clear cell and endometrioid carcinomas (Jones et al., 2010Jones S. Wang T.-L. Shih IeM. Mao T.-L. Nakayama K. Roden R. Glas R. Slamon D. Diaz Jr., L.A. 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Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy.Nat. Genet. 2013; 45: 592-601Crossref PubMed Scopus (269) Google Scholar, Shain and Pollack, 2013Shain A.H. Pollack J.R. The spectrum of SWI/SNF mutations, ubiquitous in human cancers.PLoS ONE. 2013; 8: e55119Crossref PubMed Scopus (155) Google Scholar). SMARCA4 (BRG1), a catalytic ATPase and a core subunit of SWI/SNF complexes, is mutated in several cancer types, including lung (Medina et al., 2008Medina P.P. Romero O.A. Kohno T. Montuenga L.M. Pio R. Yokota J. Sanchez-Cespedes M. Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines.Hum. Mutat. 2008; 29: 617-622Crossref PubMed Scopus (134) Google Scholar, Reisman et al., 2003Reisman D.N. Sciarrotta J. Wang W. Funkhouser W.K. Weissman B.E. 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The mechanisms by which mutation of each individual subunit promote oncogenesis and the function of mutated SWI/SNF complexes in cancer is now an active area of investigation. Many studies have elucidated pathways that are regulated by SWI/SNF complexes and how disruption of these gene expression programs by subunit mutation promotes cancer. For example, SWI/SNF can bind to retinoblastoma (RB) and facilitate repression of RB target genes (Trouche et al., 1997Trouche D. Le Chalony C. Muchardt C. Yaniv M. Kouzarides T. RB and hbrm cooperate to repress the activation functions of E2F1.Proc. Natl. Acad. Sci. USA. 1997; 94: 11268-11273Crossref PubMed Scopus (0) Google Scholar). SWI/SNF also interacts with MYC, both as an activator and as a repressor (Cheng et al., 1999Cheng S.W. Davies K.P. Yung E. Beltran R.J. Yu J. Kalpana G.V. c-MYC interacts with INI1/hSNF5 and requires the SWI/SNF complex for transactivation function.Nat. 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Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation.Cancer Cell. 2010; 18: 316-328Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar). Targeted inhibition of EZH2 may represent a therapeutic opportunity for SMARCB1 mutant cancers (Knutson et al., 2013Knutson S.K. Warholic N.M. Wigle T.J. Klaus C.R. Allain C.J. Raimondi A. Porter Scott M. Chesworth R. Moyer M.P. Copeland R.A. et al.Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2.Proc. Natl. Acad. Sci. USA. 2013; 110: 7922-7927Crossref PubMed Scopus (0) Google Scholar). While the mechanisms by which SWI/SNF mutations contribute to cancer are still being elucidated and the relative importance of contributions to transcriptional regulation versus DNA repair are still in question, mutation of SWI/SNF subunits in cancer likely contributes to cancer, at least in part, by perturbing the regulation of transcriptional pathways involved in control of proliferation and fate specification (Eroglu et al., 2014Eroglu E. Burkard T.R. Jiang Y. Saini N. Homem C.C.F. Reichert H. Knoblich J.A. SWI/SNF complex prevents lineage reversion and induces temporal patterning in neural stem cells.Cell. 2014; 156: 1259-1273Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). It is interesting to note that, while loss-of-function SWI/SNF subunit mutations seem most prevalent in cancer, point mutations have also been described, such as a small number of SMARCA4 missense mutations in medulloblastoma (Parsons et al., 2011Parsons D.W. Li M. Zhang X. Jones S. Leary R.J. Lin J.C.-H. Boca S.M. Carter H. Samayoa J. Bettegowda C. et al.The genetic landscape of the childhood cancer medulloblastoma.Science. 2011; 331: 435-439Crossref PubMed Scopus (452) Google Scholar). It is not yet understood whether these point mutations also result in loss of function of the protein, as in a classical tumor suppressor, or whether they result in partial loss, or even potentially oncogenic gain-of-function effects. Looking forward, elucidating the effects of these point mutations will likely provide further mechanistic understanding of the cancer-promoting activity of SWI/SNF mutations. However, from a therapeutic standpoint, as mutations in genes encoding SWI/SNF complex subunits are often loss of function, including nonsense, frameshift, and large deletions (Lee et al., 2012Lee R.S. Stewart C. Carter S.L. Ambrogio L. Cibulskis K. Sougnez C. Lawrence M.S. Auclair D. Mora J. Golub T.R. et al.A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers.J. Clin. Invest. 2012; 122: 2983-2988Crossref PubMed Scopus (158) Google Scholar, Versteege et al., 1998Versteege I. Sévenet N. Lange J. Rousseau-Merck M.F. Ambros P. Handgretinger R. Aurias A. Delattre O. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer.Nature. 1998; 394: 203-206Crossref PubMed Scopus (911) Google Scholar, Wang et al., 2014bWang X. Haswell J.R. Roberts C.W.M. Molecular pathways: SWI/SNF (BAF) complexes are frequently mutated in cancer—mechanisms and potential therapeutic insights.Clin. Cancer Res. 2014; 20: 21-27Crossref PubMed Scopus (54) Google Scholar, Wilson and Roberts, 2011Wilson B.G. Roberts C.W.M. SWI/SNF nucleosome remodellers and cancer.Nat. Rev. Cancer. 2011; 11: 481-492Crossref PubMed Scopus (481) Google Scholar), the products of the mutant genes themselves do not constitute obvious drug targets. Consequently, it is of great interest to identify specific vulnerabilities conferred by these mutations on cancer cells that have the potential to provide new therapeutic opportunities. One attractive hypothesis to account for many subunits of a single complex mutated is that all of the mutations are essentially equivalent and result in inactivation of SWI/SNF complexes. However, several findings seemed in conflict with such a possibility. First, the consequences of inactivation of genes encoding SWI/SNF subunits in mice are fairly distinct. For example, while inactivation of Smarcb1 and Smarca4 both result in early embryonic lethality at embryonic day (E)3.5 (Guidi et al., 2001Guidi C.J. Sands A.T. Zambrowicz B.P. Turner T.K. Demers D.A. Webster W. Smith T.W. Imbalzano A.N. Jones S.N. Disruption of Ini1 leads to peri-implantation lethality and tumorigenesis in mice.Mol. Cell. Biol. 2001; 21: 3598-3603Crossref PubMed Scopus (0) Google Scholar, Klochendler-Yeivin et al., 2000Klochendler-Yeivin A. Fiette L. Barra J. Muchardt C. Babinet C. Yaniv M. The murine SNF5/INI1 chromatin remodeling factor is essential for embryonic development and tumor suppression.EMBO Rep. 2000; 1: 500-506Crossref PubMed Google Scholar), knockout of Arid1a leads to the absence of mesoderm and arrest at E6.5 (Gao et al., 2008Gao X. Tate P. Hu P. Tjian R. Skarnes W.C. Wang Z. ES cell pluripotency and germ-layer formation require the SWI/SNF chromatin remodeling component BAF250a.Proc. Natl. Acad. Sci. USA. 2008; 105: 6656-6661Crossref PubMed Scopus (169) Google Scholar), silencing of Smarcd3 results in heart developmental defects (Lickert et al., 2004Lickert H. Takeuchi J.K. Von Both I. Walls J.R. McAuliffe F. Adamson S.L. Henkelman R.M. Wrana J.L. Rossant J. Bruneau B.G. Baf60c is essential for function of BAF chromatin remodelling complexes in heart development.Nature. 2004; 432: 107-112Crossref PubMed Scopus (307) Google Scholar), and Smarca2-deficient mice are viable (Reyes et al., 1998Reyes J.C. Barra J. Muchardt C. Camus A. Babinet C. Yaniv M. Altered control of cellular proliferation in the absence of mammalian brahma (SNF2alpha).EMBO J. 1998; 17: 6979-6991Crossref PubMed Google Scholar). Consequently, subunit loss results in distinct developmental phenotypes. Second, loss of different s
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