Chromatin Remodeling SWI/SNF complex in Cancer
Mammalian SWI/SNF chromatin remodeling complex has been found to be mutated in many different cancers arising from nearly every tissue type in the body, and in total is mutated in more than 25% of all human cancers. Despite the prevalence of SWI/SNF mutations, the contributions of these alterations to tumorigenesis remain unclear.
The central focus of our laboratory is to determine the roles of major SWI/SNF subunits, such as ARID1A, in regulating protein complex assembly and the impact of various complex compositions on chromatin targeting. We use a combination of biochemical, genomic, and epigenomic assays to understand the functions of these complexes using various model systems, with the ultimate goal of understanding the fundamental epigenetic mechanism(s) by which loss of chromatin regulatory subunits drives tumor development.
Bennett K. Wolf*, Yanding Zhao*, Andrew McCray*, William H. Hawk, Luke T. Deary, Nicholas W. Sugiarto, Ian S. LaCroix, Scott A. Gerber, Chao Cheng & Xiaofeng Wang. Cooperation of chromatin remodeling SWI/SNF complex and pioneer factor AP-1 shapes 3D enhancer landscapes. Nature Structural & Molecular Biology. 2022 Dec 15. doi: 10.1038/s41594-022-00880-x.
Wang X, Wang S, Troisi EC, Howard TP, Haswell JR, Wolf BK, Hawk WH, Ramos P, Oberlick EM, Tzvetkov EP, Vazquez F, Hahn WC, Park PJ, Roberts CWM. BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors. Nature Communications. 2019 Apr 23;10(1):188.
Wang X, Lee RS, Alver BH, Haswell JR, Wang S, Mieczkowski J, Drier Y, Gillespie SM, Archer TC, Wu JN, Tzvetkov EP, Troisi EC, Pomeroy SL, Biegel JA, Tolstorukov MY, Bernstein BE, Park PJ, Roberts CW. SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. Nature Genetics. 2017; 49(2):289-295
Mathur R, Alver BH, San Roman AK, Wilson BG, Wang X, Agoston AT, Park PJ, Shivdasani RA, Roberts CW. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nature Genetics. 2017; 49(2):296-302.
Helming KC*, Wang X*, Roberts CW. Vulnerabilities of Mutant SWI/SNF Complexes in Cancer. Cancer Cell. 2014 Sep 8;26 (3):309-317 (*Co-first author)
Helming KC, Wang X*, Wilson BG, Vazquez F, Haswell JR, Manchester HE, Kim Y, Kryukov GV, Ghandi M, Aguirre AJ, Jagani Z, Wang Z, Garraway LA, Hahn WC, Roberts CW. ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nature Medicine, 2014 Mar;20 (3):251-4. (*Co-first author). (*Co-first author)
Alver BH, Kim KH, Lu P, Wang X, Manchester HE, Wang W, Haswell JR, Park PJ, Roberts CW. The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers. Nature Communications. 2017; 8:14648.
Vierbuchen T, Ling E, Cowley CJ, Couch CH, Wang X, Harmin DA, Roberts CWM, Greenberg ME. AP-1 Transcription Factors and the BAF Complex Mediate Signal-Dependent Enhancer Selection. Molecular Cell. 2017, 68(6):1067-1082.
Howard TP, Arnoff TE, Song MR, Giacomelli AO, Wang X, Hong AL, Dharia NV, Wang S, Vazquez F, Pham MT, Morgan AM, Wachter F, Bird GH, Kugener G, Oberlick EM, Rees MG, Tiv HL, Hwang JH, Walsh KH, Cook A, Krill-Burger JM, Tsherniak A, Gokhale PC, Park PJ, Stegmaier K, Walensky LD, Hahn WC, Roberts CWM. MDM2 and MDM4 Are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors. Cancer Research. 2019 May 1;79(9):2404-2414.