The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation

Abstract

// 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.