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Mol Cell. 2015 Aug 6;59(3):345-358. doi: 10.1016/j.molcel.2015.05.037. Epub 2015 Jul 2.

Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling.

Author information

1
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
2
Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois 60637, USA.
3
Department of Dermatology, Emory University, Atlanta, Georgia 30322, USA.
4
Atlanta Veterans Administration Medical Center, Atlanta, Georgia 30322, USA.
5
Department of Pathology and Laboratory Medicine.
6
Division of Molecular Biology and Biochemistry, University of Missouri, Kansas City, MO 64110, USA.
7
Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
8
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.
9
Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
10
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
11
School of Pharmacy, Fudan University, Shanghai 201203, China.
12
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
13
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
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Contributed equally

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.

PMID:
26145173
PMCID:
PMC4530073
DOI:
10.1016/j.molcel.2015.05.037
[Indexed for MEDLINE]
Free PMC Article

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