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Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers

2014; National Academy of Sciences; Volume: 111; Issue: 8 Linguagem: Inglês

10.1073/pnas.1316793111

1091-6490

Gregory R. Hoffman, Rami Rahal, Frank P. Buxton, Kay X. Xiang, Gregory McAllister, Elizabeth Frias, Linda Bagdasarian, Janina Huber, Alicia Lindeman, Dongshu Chen, Rodrigo Romero, Nadire Ramadan, Tanushree Phadke, Kristy Haas, Mariela Jaskelioff, Boris G. Wilson, Matthew J. Meyer, Veronica Saenz-Vash, Huili Zhai, Vic E. Myer, Jeffery A. Porter, Nicholas Keen, Margaret E. McLaughlin, Craig Mickanin, Charles W.M. Roberts, Frank Stegmeier, Zainab Jagani,

Mechanisms of cancer metastasis

Significance Mammalian SWI/SNF (mSWI/SNF) alterations are highly prevalent, now estimated to occur in 20% of cancers. The inactivating nature of mSWI/SNF mutations presents a challenge for devising strategies to target these epigenetic lesions. By performing a comprehensive pooled shRNA screen of the epigenome using a unique deep coverage design shRNA (DECODER) library across a large cancer cell line panel, we identified that BRG1/SMARCA4 mutant cancer cells are highly sensitive to BRM/SMARCA2 depletion. Our study provides important mechanistic insight into the BRM/BRG1 synthetic lethal relationship, shows this finding translates in vivo, and highlights BRM as a promising therapeutic target for the treatment BRG1 -mutant cancers.