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

Mol Cell
Authors
Keywords
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.

Year of Publication
2015
Journal
Mol Cell
Volume
59
Issue
3
Pages
345-58
Date Published
2015 Aug 06
ISSN
1097-4164
URL
DOI
10.1016/j.molcel.2015.05.037
PubMed ID
26145173
PubMed Central ID
PMC4530073
Links
Grant list
R01 GM074024 / GM / NIGMS NIH HHS / United States
T32 GM008602 / GM / NIGMS NIH HHS / United States
CA183594 / CA / NCI NIH HHS / United States
CA175316 / CA / NCI NIH HHS / United States
R01 GM071440 / GM / NIGMS NIH HHS / United States
CA140515 / CA / NCI NIH HHS / United States
R01 CA174786 / CA / NCI NIH HHS / United States
R01 CA140515 / CA / NCI NIH HHS / United States
R01 CA175316 / CA / NCI NIH HHS / United States
CA174786 / CA / NCI NIH HHS / United States
R01 CA183594 / CA / NCI NIH HHS / United States
R01 CA121941 / CA / NCI NIH HHS / United States
R01 AR047901 / AR / NIAMS NIH HHS / United States
R01 CA190394 / CA / NCI NIH HHS / United States
AR47901 / AR / NIAMS NIH HHS / United States
GM071440 / GM / NIGMS NIH HHS / United States