Activated BRAF suppresses oxidative metabolism in melanoma via inhibition of MITF and PGC1α.

  • Major finding: Activated BRAF suppresses oxidative metabolism in melanoma via inhibition of MITF and PGC1α.

  • Mechanism: BRAF inhibitors induce MITF-dependent PGC1α expression and addiction to oxidative metabolism.

  • Impact: Combined treatment with mitochondrial uncouplers may improve the efficacy of BRAF inhibitors.

Metabolic alterations in cancer cells promote a switch from oxidative phosphorylation to an increased dependence on aerobic glycolysis, known as the Warburg effect. Dysregulation of oncogenes has been implicated in this metabolic reprogramming in many solid tumors, but the role of oncogenic BRAF in the regulation of this adaptive program in melanoma is unknown. Haq and colleagues found that BRAF inhibitor treatment resulted in elevated expression of genes involved in oxidative phosphorylation specifically in BRAF-mutant melanomas. Furthermore, BRAF inhibition increased both mitochondrial number and function and decreased lactate levels in BRAF-mutant melanoma cells, suggesting that activated BRAF suppresses mitochondrial respiration. In support of this idea, blockade of BRAF or MAP/ERK kinase (MEK) signaling augmented the mRNA expression of peroxisome proliferator-activated receptor γ, coactivator 1α (PPARGC1A, also known as PGC1α), a master regulator of mitochondrial metabolism, in melanoma cell lines and primary patient samples. This stimulation of PGC1α expression in melanoma cells in response to BRAF inhibition was mediated by relief of BRAF-dependent negative regulation of microphthalmia-associated transcription factor (MITF), which bound to the proximal PGC1α promoter and was required for PGC1α induction. MITF expression in primary BRAF-mutant melanocytes was sufficient to trigger expression of oxidative phosphorylation genes, resulting in reduced lactate production, enhanced oxygen consumption, and increased sensitivity to mitochondrial uncouplers such as 2,4-dinitrophenol. Moreover, MITF and PGC1α expression enabled sustained ATP production and cell viability following BRAF blockade, suggesting that BRAF-inhibited cells become addicted to oxidative phosphorylation. Indeed, mitochondrial uncouplers impaired melanoma xenograft growth and increased the cytotoxic effects of BRAF inhibition in vitro. These results identify oncogenic BRAF as a critical regulator of tumor metabolism and suggest a combinatorial therapeutic strategy that may improve the efficacy of BRAF inhibitors in patients with melanoma.

Haq R, Shoag J, Andreu-Perez P, Yokoyama S, Edelman H, Rowe GC, et al. Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. Cancer Cell 2013 Mar 7 [Epub ahead of print].