Wilson, BG, Helming, KC, Wang, X, Kim, Y, Vazquez, F, Jagani, Z, Hahn, WC and Roberts, CWM (2014) Residual Complexes Containing SMARCA2 (BRM) Underlie the Oncogenic Drive of SMARCA4 (BRG1) Mutation. MOLECULAR AND CELLULAR BIOLOGY. pp. 1136-1144.

Abstract

Collectively, genes encoding subunits of the SWI/SNF (BAF) chromatin remodeling complex are mutated in 20% of all human cancers, with the SMARCA4 (BRG1) subunit being one of the most frequently mutated. The SWI/SNF complex modulates chromatin remodeling through the activity of two mutually exclusive catalytic subunits, SMARCA4 and SMARCA2 (BRM). Here, we show that a SMARCA2-containing residual SWI/SNF complex underlies the oncogenic activity of SMARCA4 mutant cancers. We demonstrate that a residual SWI/SNF complex exists in SMARCA4 mutant cell lines and plays essential roles in cellular proliferation. Further, using data from loss-of-function screening of 165 cancer cell lines, we identify SMARCA2 as an essential gene in SMARCA4 mutant cancer cell lines. Mechanistically, we reveal that Smarca4 inactivation leads to greater incorporation of the nonessential SMARCA2 subunit into the SWI/SNF complex. Collectively, these results reveal a role for SMARCA2 in oncogenesis caused by SMARCA4 loss and identify the ATPase and bromodomain-containing SMARCA2 as a potential therapeutic target in these cancers

Item Type:	Article
Additional Information:	NIBR author: Jagani, Z institute: NIBR contributor address: Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA ; Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA, Broad Inst Harvard & MIT, Canc Program, Boston, MA USA ; Novartis Inst BioMed Res, Cambridge, MA USA ; Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA, Broad Inst Harvard & MIT, Canc Program, Boston, MA USA, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA ; Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA, Broad Inst Harvard & MIT, Canc Program, Boston, MA USA, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA charles_roberts@dfci.harvard.edu; Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA; Roberts, CWM; Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/22615