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

doi:10.1016/j.ccr.2013.02.003

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 journal › Article › peer-review

635 Scopus citations

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 language	English (US)
Pages (from-to)	302-315
Number of pages	14
Journal	Cancer Cell
Volume	23
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2013.02.003
State	Published - Mar 18 2013
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

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@article{bc2ba4d29ca64704879c5d2e611be9e5,

title = "Oncogenic BRAF regulates oxidative metabolism via PGC1α 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, 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.",

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

note = "Funding Information: We thank A. Winant for assistance with manuscript writing, M. McKee for electron microscopy, and A. Saur at the Luria Family Imaging Center (Dana-Farber Cancer Institute) for assistance with mouse xenograft experiments. This work was supported by the American Skin Association (to R.H.), NIAMS/NIH (R01 AR043369-16), Melanoma Research Alliance, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to D.E.F.), and The National Cancer Institute (R01CA163336 to J.S.S. and P50CA093683 to H.R.W.). ",

year = "2013",

month = mar,

day = "18",

doi = "10.1016/j.ccr.2013.02.003",

language = "English (US)",

volume = "23",

pages = "302--315",

journal = "Cancer Cell",

issn = "1535-6108",

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T1 - Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF

AU - Haq, Rizwan

AU - Shoag, Jonathan

AU - Andreu-Perez, Pedro

AU - Yokoyama, Satoru

AU - Edelman, Hannah

AU - Rowe, Glenn C.

AU - Frederick, Dennie T.

AU - Hurley, Aeron D.

AU - Nellore, Abhinav

AU - Kung, Andrew L.

AU - Wargo, Jennifer A.

AU - Song, Jun S.

AU - Fisher, David E.

AU - Arany, Zolt

AU - Widlund, Hans R.

N1 - Funding Information: We thank A. Winant for assistance with manuscript writing, M. McKee for electron microscopy, and A. Saur at the Luria Family Imaging Center (Dana-Farber Cancer Institute) for assistance with mouse xenograft experiments. This work was supported by the American Skin Association (to R.H.), NIAMS/NIH (R01 AR043369-16), Melanoma Research Alliance, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to D.E.F.), and The National Cancer Institute (R01CA163336 to J.S.S. and P50CA093683 to H.R.W.).

PY - 2013/3/18

Y1 - 2013/3/18

N2 - 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.

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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SP - 302

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JO - Cancer Cell

JF - Cancer Cell

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Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF

Abstract

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