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

Hee Bum Kang, Jun Fan, Ruiting Lin, Shannon Elf, Quanjiang Ji, Liang Zhao, Lingtao Jin, Jae Ho Seo, Changliang Shan, Jack L. Arbiser, Cynthia Cohen, Daniel Brat, Henry M. Miziorko, Eunhee Kim, Omar Abdel-Wahab, Taha Merghoub, Stefan Fröhling, Claudia Scholl, Pablo Tamayo, David A. BarbieLu Zhou, Brian P. Pollack, Kevin Fisher, Ragini R. Kudchadkar, David H. Lawson, Gabriel Sica, Michael Rossi, Sagar Lonial, Hanna J. Khoury, Fadlo R. Khuri, Benjamin H. Lee, Titus J. Boggon, Chuan He, Sumin Kang*, Jing Chen

*Corresponding author for this work

Research output: Contribution to journalArticle

69 Scopus citations

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. Many cancers share common metabolic alterations, yet how such alterations contribute to tumor development remains unclear. Kang etal. demonstrate a "synthetic lethal" interaction between oncogenic BRAF V600E and a ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) that promotes BRAF V600E-dependent tumor development.

Original languageEnglish (US)
Pages (from-to)345-358
Number of pages14
JournalMolecular Cell
Volume59
Issue number3
DOIs
StatePublished - Aug 6 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Kang, H. B., Fan, J., Lin, R., Elf, S., Ji, Q., Zhao, L., Jin, L., Seo, J. H., Shan, C., Arbiser, J. L., Cohen, C., Brat, D., Miziorko, H. M., Kim, E., Abdel-Wahab, O., Merghoub, T., Fröhling, S., Scholl, C., Tamayo, P., ... Chen, J. (2015). Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling. Molecular Cell, 59(3), 345-358. https://doi.org/10.1016/j.molcel.2015.05.037