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Oncogenic BRAF regulates oxidative metabolism via PGC1? and MITF.

ABSTRACT: Activating mutations in BRAF are the most common genetic alterations in melanoma. Inhibition of BRAF by small molecules 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, PGC1?. We further show that a target of BRAF, the melanocyte lineage factor MITF, directly regulates the expression of PGC1?. Melanomas with activation of the BRAF/MAPK pathway have suppressed levels of MITF and PGC1? 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.

SUBMITTER: Haq R

PROVIDER: S-EPMC3635826 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF.

Haq Rizwan R Shoag Jonathan J Andreu-Perez Pedro P Yokoyama Satoru S Edelman Hannah H Rowe Glenn C GC Frederick Dennie T DT Hurley Aeron D AD Nellore Abhinav A Kung Andrew L AL Wargo Jennifer A JA Song Jun S JS Fisher David E DE Arany Zolt Z Widlund Hans R HR

Cancer cell 20130307 3

Activating mutations in BRAF are the most common genetic alterations in melanoma. Inhibition of BRAF by small molecules 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 ...[more]

PMID: 23477830

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Oncogenic BRAF regulates oxidative metabolism via PGC1? and MITF

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Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF

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