Targeting the chromatin remodeling enzyme BRG1 increases the efficacy of chemotherapy drugs in breast cancer cells
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Qiong Wu1, Soni Sharma2, Hang Cui1,3, Scott E. LeBlanc1, Hong Zhang1, Rohini Muthuswami2, Jeffrey A. Nickerson1 and Anthony N. Imbalzano1
1 Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA
2 School of Life Sciences, Jawaharlal Nehru University, New Delhi, Delhi, India
3 Abace Biotech Co Ltd., Yi Zhuang Biomedical Park, BDA, Beijing, China
Jeffrey A. Nickerson, email:
Anthony N. Imbalzano, email:
Keywords: epigenetics, BRG1, SWI/SNF, breast cancer, drug transporters
Received: September 22, 2015 Accepted: March 16, 2016 Published: March 25, 2016
Brahma related gene product 1 (BRG1) is an ATPase that drives the catalytic activity of a subset of the mammalian SWI/SNF chromatin remodeling enzymes. BRG1 is overexpressed in most human breast cancer tumors without evidence of mutation and is required for breast cancer cell proliferation. We demonstrate that knockdown of BRG1 sensitized triple negative breast cancer cells to chemotherapeutic drugs used to treat breast cancer. An inhibitor of the BRG1 bromodomain had no effect on breast cancer cell viability, but an inhibitory molecule that targets the BRG1 ATPase activity recapitulated the increased drug efficacy observed in the presence of BRG1 knockdown. We further demonstrate that inhibition of BRG1 ATPase activity blocks the induction of ABC transporter genes by these chemotherapeutic drugs and that BRG1 binds to ABC transporter gene promoters. This inhibition increased intracellular concentrations of the drugs, providing a likely mechanism for the increased chemosensitivity. Since ABC transporters and their induction by chemotherapy drugs are a major cause of chemoresistance and treatment failure, these results support the idea that targeting the enzymatic activity of BRG1 would be an effective adjuvant therapy for breast cancer.
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