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// Qiong Wu 1 , Pasil Madany 1 , Jason R. Dobson 1 , Jake M. Schnabl 1 , Soni Sharma 2 , Tara C. Smith 1 Andre J. van Wijnen 3 , Janet L. Stein 4 , Jane B. Lian 4 , Gary S. Stein 4 , Rohini Muthuswami 2 , Anthony N. Imbalzano 1 , Jeffrey A. Nickerson 1 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 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA 4 Department of Biochemistry and Vermont Cancer Center for Basic and Translational Research, University of Vermont College of Medicine, Burlington, WA, USA Correspondence to: Anthony N. Imbalzano, email: anthony.imbalzano@umassmed.edu Jeffrey A. Nickerson, email: jeffrey.nickerson@umassmed.edu Keywords: breast cancer, metabolism, lipogenesis, gene regulation, BRG1 Received: January 07, 2016 Accepted: May 01, 2016 Published: May 20, 2016 ABSTRACT Cancer cells reprogram cellular metabolism to meet the demands of growth. Identification of the regulatory machinery that regulates cancer-specific metabolic changes may open new avenues for anti-cancer therapeutics. The epigenetic regulator BRG1 is a catalytic ATPase for some mammalian SWI/SNF chromatin remodeling enzymes. BRG1 is a well-characterized tumor suppressor in some human cancers, but is frequently overexpressed without mutation in other cancers, including breast cancer. Here we demonstrate that BRG1 upregulates de novo lipogenesis and that this is crucial for cancer cell proliferation. Knockdown of BRG1 attenuates lipid synthesis by impairing the transcription of enzymes catalyzing fatty acid and lipid synthesis. Remarkably, exogenous addition of palmitate, the key intermediate in fatty acid synthesis, rescued the cancer cell proliferation defect caused by BRG1 knockdown. Our work suggests that targeting BRG1 to reduce lipid metabolism and, thereby, to reduce proliferation, has promise for epigenetic therapy in triple negative breast cancer.

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.