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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetoacetates / metabolism
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Leukemia, Hairy Cell / metabolism*
  • MAP Kinase Kinase 1 / metabolism*
  • Melanoma / metabolism*
  • Mutation
  • Octamer Transcription Factor-1 / metabolism*
  • Oxo-Acid-Lyases / metabolism*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism*
  • Signal Transduction*
  • Up-Regulation


  • Acetoacetates
  • Octamer Transcription Factor-1
  • POU2F1 protein, human
  • acetoacetic acid
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Oxo-Acid-Lyases
  • 3-hydroxy-3-methylglutaryl-coenzyme A lyase