title: The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation.
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.
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Pasil
authors.initials: P
authors.lastname: Madany
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Dobson
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Jake M
authors.initials: JM
authors.lastname: Schnabl
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Delhi, Delhi, India.
authors.forename: Soni
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Tara C
authors.initials: TC
authors.lastname: Smith
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.affiliation: Department of Biochemistry and Vermont Cancer Center for Basic and Translational Research, University of Vermont College of Medicine, Burlington, WA, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.affiliation: Department of Biochemistry and Vermont Cancer Center for Basic and Translational Research, University of Vermont College of Medicine, Burlington, WA, USA.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.affiliation: Department of Biochemistry and Vermont Cancer Center for Basic and Translational Research, University of Vermont College of Medicine, Burlington, WA, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Delhi, Delhi, India.
authors.forename: Rohini
authors.initials: R
authors.lastname: Muthuswami
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Imbalzano
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Nickerson
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002843:Chromatin / Q000378:metabolism*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008055:Lipids / Q000096:biosynthesis; D050155:Lipogenesis; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D008055:Lipids; D009687:Nuclear Proteins; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases
keywords: BRG1; breast cancer; gene regulation; lipogenesis; metabolism