Oncogenic BRAF Regulates Oxidative Metabolism via PGC1α and MITF

Abstract

Summary Activating mutations in BRAF are the most common genetic alterations in melanoma. Inhibition of BRAF by small molecule inhibitors leads to cell cycle arrest and apoptosis. We show here that BRAF inhibition also induces an oxidative phosphorylation gene program, mitochondrial biogenesis, and the increased expression of the mitochondrial master regulator, PGC1α. We further show that a target of BRAF, the melanocyte lineage factor MITF, directly regulates the expression of PGC1α. Melanomas with activation of the BRAF/MAPK pathway have suppressed levels of MITF and PGC1α, and decreased oxidative metabolism. Conversely, treatment of BRAF mutated melanomas with BRAF inhibitors renders them addicted to oxidative phosphorylation. Our data thus identify an adaptive metabolic program that limits the efficacy of BRAF inhibitors.

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…Restoration of MITF expression in melanoma cells after inhibition of mutant BRAF has been associated with increased expression of the downstream antiapoptotic protein BCL2A1 (REF. 130), as well as peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α), a master regulator of mitochondrial biogenesis and, thus, oxidative phosphorylation 131 (FIG. 4a).…”

Metabolic Dysregulation in Melanoma: Cause or Consequence?

“…The most obvious danger is augmenting mitochondrial function that in some cases may support the bioenergetic demands of the melanoma cells ( 3 ). DCA has been shown to alter mitochondria when given to patients in clinical trials.…”

A short acidic motif in ARF guards against mitochondrial dysfunction and melanoma susceptibility

“…Our data show that this apparent paradox should probably be viewed in the context of the fundamental changes in metabolism that occur during melanoma development. Mutated BRAF, when acting as an early melanoma driver, promotes metabolic reprogramming by suppressing oxidative phosphorylation and promoting glycolysis 32,33 . Consistent with a 'watching and waiting' function of ARF, its growth-inhibitory function was inactive in BRAF V600E /ARFexpressing melanoma cells, but could be induced in vitro and in vivo by redirecting the metabolism toward mitochondrial oxidative metabolism.…”

“…Previous studies have shown that inhibition of oncogenic BRAF E600 in melanoma cells causes a redirection of metabolism towards the compensatory use of oxidative phosphorylation 32,33 . To study if a metabolic shift could lead to the activation of ARF by unmasking mitochondrial dysfunction inherently present in melanoma cells, we treated ARF-proficient melanoma cells with the glycolysis inhibitor 2-deoxy-D-glucose (2-DG).…”