title: Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling.
abstract: Many human cancers share similar metabolic alterations, including the Warburg effect. However, it remains unclear whether oncogene-specific metabolic alterations are required for tumor development. Here we demonstrate a "synthetic lethal" interaction between oncogenic BRAF V600E and a ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL). HMGCL expression is upregulated in BRAF V600E-expressing human primary melanoma and hairy cell leukemia cells. Suppression of HMGCL specifically attenuates proliferation and tumor growth potential of human melanoma cells expressing BRAF V600E. Mechanistically, active BRAF upregulates HMGCL through an octamer transcription factor Oct-1, leading to increased intracellular levels of HMGCL product, acetoacetate, which selectively enhances binding of BRAF V600E but not BRAF wild-type to MEK1 in V600E-positive cancer cells to promote activation of MEK-ERK signaling. These findings reveal a mutation-specific mechanism by which oncogenic BRAF V600E "rewires" metabolic and cell signaling networks and signals through the Oct-1-HMGCL-acetoacetate axis to selectively promote BRAF V600E-dependent tumor development.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Hee-Bum
authors.initials: HB
authors.lastname: Kang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Ruiting
authors.initials: R
authors.lastname: Lin
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Elf
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Quanjiang
authors.initials: Q
authors.lastname: Ji
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Lingtao
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Seo
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Changliang
authors.initials: C
authors.lastname: Shan
authors.affiliation: Department of Dermatology, Emory University, Atlanta, Georgia 30322, USA.|Atlanta Veterans Administration Medical Center, Atlanta, Georgia 30322, USA.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Cohen
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Daniel
authors.initials: D
authors.lastname: Brat
authors.affiliation: Division of Molecular Biology and Biochemistry, University of Missouri, Kansas City, MO 64110, USA.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Miziorko
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Section for Personalized Oncology, Heidelberg University Hospital, German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Scholl
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Tamayo
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Barbie
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Dermatology, Emory University, Atlanta, Georgia 30322, USA.|Atlanta Veterans Administration Medical Center, Atlanta, Georgia 30322, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Pollack
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Kevin
authors.initials: K
authors.lastname: Fisher
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Ragini R
authors.initials: RR
authors.lastname: Kudchadkar
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Lawson
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Sica
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Hanna J
authors.initials: HJ
authors.lastname: Khoury
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Sumin
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
mesh_terms: D000090:Acetoacetates / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007943:Leukemia, Hairy Cell / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism*; D009154:Mutation; D050811:Octamer Transcription Factor-1 / Q000378:metabolism*; D007652:Oxo-Acid-Lyases / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D000090:Acetoacetates; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; C016635:acetoacetic acid; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D007652:Oxo-Acid-Lyases; C021410:3-hydroxy-3-methylglutaryl-coenzyme A lyase