Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF

Rizwan Haq, Jonathan Shoag, Pedro Andreu-Perez, Satoru Yokoyama, Hannah Edelman, Glenn C. Rowe, Dennie T. Frederick, Aeron D. Hurley, Abhinav Nellore, Andrew L. Kung, Jennifer A. Wargo, Jun S. Song, David E. Fisher, Zolt Arany, Hans R. Widlund

Research output: Contribution to journalArticle

373 Citations (Scopus)

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, 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.

Original languageEnglish (US)
Pages (from-to)302-315
Number of pages14
JournalCancer Cell
Volume23
Issue number3
DOIs
StatePublished - Mar 18 2013
Externally publishedYes

Fingerprint

Melanoma
Oxidative Phosphorylation
Melanocytes
Organelle Biogenesis
Cell Cycle Checkpoints
Apoptosis
Mutation
Genes

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Haq, R., Shoag, J., Andreu-Perez, P., Yokoyama, S., Edelman, H., Rowe, G. C., ... Widlund, H. R. (2013). Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. Cancer Cell, 23(3), 302-315. https://doi.org/10.1016/j.ccr.2013.02.003

Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. / Haq, Rizwan; Shoag, Jonathan; Andreu-Perez, Pedro; Yokoyama, Satoru; Edelman, Hannah; Rowe, Glenn C.; Frederick, Dennie T.; Hurley, Aeron D.; Nellore, Abhinav; Kung, Andrew L.; Wargo, Jennifer A.; Song, Jun S.; Fisher, David E.; Arany, Zolt; Widlund, Hans R.

In: Cancer Cell, Vol. 23, No. 3, 18.03.2013, p. 302-315.

Research output: Contribution to journalArticle

Haq, R, Shoag, J, Andreu-Perez, P, Yokoyama, S, Edelman, H, Rowe, GC, Frederick, DT, Hurley, AD, Nellore, A, Kung, AL, Wargo, JA, Song, JS, Fisher, DE, Arany, Z & Widlund, HR 2013, 'Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF', Cancer Cell, vol. 23, no. 3, pp. 302-315. https://doi.org/10.1016/j.ccr.2013.02.003
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 18;23(3):302-315. https://doi.org/10.1016/j.ccr.2013.02.003
Haq, Rizwan ; Shoag, Jonathan ; Andreu-Perez, Pedro ; Yokoyama, Satoru ; Edelman, Hannah ; Rowe, Glenn C. ; Frederick, Dennie T. ; Hurley, Aeron D. ; Nellore, Abhinav ; Kung, Andrew L. ; Wargo, Jennifer A. ; Song, Jun S. ; Fisher, David E. ; Arany, Zolt ; Widlund, Hans R. / Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. In: Cancer Cell. 2013 ; Vol. 23, No. 3. pp. 302-315.
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AB - 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 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.

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