Metabolic rewiring by oncogenic BRAF V600E links ketogenesis pathway to BRAF-MEK1 signaling Journal Article


Authors: 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.; Barbie, David; Zhou, L.; Pollack, B. P.; Fisher, K.; Kudchadkar, R. R.; Lawson, D. H.; Sica, G.; Rossi, M.; Lonial, S.; Khoury, H. J.; Khuri, F. R.; Lee, B. H.; Boggon, T. J.; He, C.; Kang, S.; Chen, J.
Article 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. 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. © 2015 Elsevier Inc.
Keywords: signal transduction; controlled study; protein expression; protein phosphorylation; human cell; promoter region; nonhuman; cell proliferation; mouse; mitogen activated protein kinase kinase 1; animal experiment; animal model; enzyme activation; tumor xenograft; carcinogenesis; leukemia cell; melanoma cell; tumor growth; b raf kinase; short hairpin rna; hairy cell leukemia; octamer transcription factor 1; human; article; acetoacetic acid; hydroxymethylglutaryl coenzyme a lyase; a375 cell line; ketogenesis
Journal Title: Molecular Cell
Volume: 59
Issue: 3
ISSN: 1097-2765
Publisher: Cell Press  
Date Published: 2015-08-06
Start Page: 345
End Page: 358
Language: English
DOI: 10.1016/j.molcel.2015.05.037
PROVIDER: scopus
PMCID: PMC4530073
PUBMED: 26145173
DOI/URL:
Notes: Export Date: 2 September 2015 -- Source: Scopus
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MSK Authors
  1. Taha Merghoub
    209 Merghoub
  2. Eunhee Kim
    28 Kim