The ketogenic enzyme HMG-CoA lyase (HMGCL) is a synthetic lethal partner of BRAFV600E in melanoma.

  • Major finding: The ketogenic enzyme HMG-CoA lyase (HMGCL) is a synthetic lethal partner of BRAFV600E in melanoma.

  • Mechanism: HMGCL upregulation by BRAFV600E increases acetoacetate, which promotes BRAFV600E–MEK1 binding.

  • Impact: HMGCL may represent an alternative therapeutic target in BRAFV600E-positive cancers.

More than half of human melanomas express oncogenic BRAFV600E, which promotes cell proliferation via BRAF–MEK1 signaling. Mutant BRAF and MEK inhibitors have shown success in clinical trials for BRAFV600E-positive melanoma, but drug resistance limits their long-term efficacy. Using systematic RNA interference screens, Kang, Fan, Lin, and colleagues identified the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) as a synthetic lethal partner of BRAFV600E in melanoma cells. HMGCL was upregulated in BRAFV600E-expressing melanoma cell lines and in primary BRAFV600E-positive melanoma and hairy cell leukemia tumors compared with BRAF wild-type–expressing samples. Knockdown of HMGCL attenuated cell proliferation in BRAFV600E-mutant cells but not in BRAF wild-type cells and decreased phosphorylation of MEK1 and ERK1/2, suggesting that HMGCL activity in ketogenesis specifically regulates the BRAF–MEK–ERK signaling cascade to promote BRAFV600E-induced transformation. HMGCL depletion led to decreased intracellular levels of its metabolic product, acetoacetate (AA), and addition of AA selectively restored cell proliferation and phosphorylation of MEK1 and ERK1/2 only in BRAFV600E-expressing cells. Mechanistically, treatment with AA increased BRAFV600E–MEK1 binding and BRAFV600E-dependent phosphorylation of MEK1 in a dose-dependent manner via direct interaction with BRAFV600E. BRAF inhibition resulted in decreased HMGCL mRNA levels, whereas MEK1 inhibition did not, suggesting that active BRAFV600E upregulates HMGCL independent of MEK1–ERK signaling. Consistent with this idea, active BRAF stimulated binding of the transcription factor OCT1 to the HMGCL promoter, and OCT1 knockdown resulted in decreased HMGCL expression in BRAFV600E-mutant cells but not in BRAF wild-type cells. Taken together, these findings suggest a mutation-specific mechanism of melanoma cell proliferation by which active BRAFV600E upregulates HMGCL via OCT1, leading to increased production of AA, which in turn promotes BRAFV600E–MEK1 binding. These results link the ketogenic pathway to BRAF–MEK1 signaling in cancer cells and suggest that HMGCL inhibition may represent a potential alternative therapy for BRAFV600E-positive cancers.

Kang HB, Fan J, Lin R, Elf S, Ji Q, Zhao L, et al. Metabolic rewiring by oncogenic BRAF V600E links ketogenesis pathway to BRAF-MEK1 signaling. Mol Cell 2015 Jul 2 [Epub ahead of print].