title: Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF.
abstract: Activating mutations in BRAF are the most common genetic alterations in melanoma. Inhibition of BRAF by small molecules leads to cell-cycle arrest and apoptosis. We show here that BRAF inhibition also induces an oxidative phosphorylation gene program, mitochondrial biogenesis, and the increased expression of the mitochondrial master regulator, PGC1α. We further show that a target of BRAF, the melanocyte lineage factor MITF, directly regulates the expression of PGC1α. Melanomas with activation of the BRAF/MAPK pathway have suppressed levels of MITF and PGC1α and decreased oxidative metabolism. Conversely, treatment of BRAF-mutated melanomas with BRAF inhibitors renders them addicted to oxidative phosphorylation. Our data thus identify an adaptive metabolic program that limits the efficacy of BRAF inhibitors.
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Haq
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shoag
authors.forename: Pedro
authors.initials: P
authors.lastname: Andreu-Perez
authors.forename: Satoru
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Hannah
authors.initials: H
authors.lastname: Edelman
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Rowe
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.forename: Aeron D
authors.initials: AD
authors.lastname: Hurley
authors.forename: Abhinav
authors.initials: A
authors.lastname: Nellore
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.forename: Jun S
authors.initials: JS
authors.lastname: Song
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.forename: Zolt
authors.initials: Z
authors.lastname: Arany
authors.forename: Hans R
authors.initials: HR
authors.lastname: Widlund
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000077484:Vemurafenib
chemical_list: D006360:Heat-Shock Proteins; D007211:Indoles; D051739:Microphthalmia-Associated Transcription Factor; C528407:PLX 4720; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D013449:Sulfonamides; D014157:Transcription Factors; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases