Oncogenic BRAF Regulates Oxidative Metabolism via PGC1α and MITF
Open accessAbstract
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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Human melanoma has two distinct subgroups: a conventional glycolytic group and a group with high oxidative phosphorylation rates.
“recent studies have identified two distinct sub-groups in human melanoma: a conventional glycolytic group and a group characterised by high rates of oxidative phosphorylation 47,48 .”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [47]
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References 79 · Cited by 818
- Authors
- Haq, R., Shoag, J., Andreu-Perez, P., Yokoyama, S., Edelman, H., Rowe, G. C., Frederick, D. T., Hurley, A. D., Nellore, A., Kung, A. L., Wargo, J. A., Song, J. S., Fisher, D. E., Arany, Z., & Widlund, H. R.
- Affiliations
- Massachusetts General Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Brigham and Women's Hospital (US)
- University of California, San Francisco (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Fisher, David E.
- Widlund, Hans R.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 23
- Issue
- 3
- Pages
- 302-315
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3635826
- OpenAlex
- W2033708806
- Cited by
- 818
- References
- 79
- Citations by year
- 2026: 32 · 2025: 46 · 2024: 63 · 2023: 49 · 2022: 68 · 2021: 76 · 2020: 83 · 2019: 76 · 2018: 67 · 2017: 68 · 2016: 65 · 2015: 53 · 2014: 50 · 2013: 21
- FWCI
- 28.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (24700971)
- National Cancer Institute (P50CA093683, R01CA163336, P01CA163222)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR043369)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- BRAF, melanoma, PGC-1α, MITF, oxidative phosphorylation, mitochondrial biogenesis, oxidative metabolism, BRAF inhibitors, MAPK signaling
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Vemurafenib, Heat-Shock Proteins, Humans, Indoles, Melanocytes, Melanoma, Mitochondria, Mutation, Oxidative Phosphorylation, RNA, Messenger, Sulfonamides, Transcription Factors, Signal Transduction, Gene Expression Regulation, Neoplastic, Apoptosis, Mitogen-Activated Protein Kinases, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Microphthalmia-Associated Transcription Factor
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