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Nature. 2016 Sep 15;537(7620):422-426. doi: 10.1038/nature19347. Epub 2016 Aug 31.

A PGC1α-mediated transcriptional axis suppresses melanoma metastasis.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
2
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
3
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
4
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
6
Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Abstract

Melanoma is the deadliest form of commonly encountered skin cancer because of its rapid progression towards metastasis. Although metabolic reprogramming is tightly associated with tumour progression, the effect of metabolic regulatory circuits on metastatic processes is poorly understood. PGC1α is a transcriptional coactivator that promotes mitochondrial biogenesis, protects against oxidative stress and reprograms melanoma metabolism to influence drug sensitivity and survival. Here, we provide data indicating that PGC1α suppresses melanoma metastasis, acting through a pathway distinct from that of its bioenergetic functions. Elevated PGC1α expression inversely correlates with vertical growth in human melanoma specimens. PGC1α silencing makes poorly metastatic melanoma cells highly invasive and, conversely, PGC1α reconstitution suppresses metastasis. Within populations of melanoma cells, there is a marked heterogeneity in PGC1α levels, which predicts their inherent high or low metastatic capacity. Mechanistically, PGC1α directly increases transcription of ID2, which in turn binds to and inactivates the transcription factor TCF4. Inactive TCF4 causes downregulation of metastasis-related genes, including integrins that are known to influence invasion and metastasis. Inhibition of BRAFV600E using vemurafenib, independently of its cytostatic effects, suppresses metastasis by acting on the PGC1α-ID2-TCF4-integrin axis. Together, our findings reveal that PGC1α maintains mitochondrial energetic metabolism and suppresses metastasis through direct regulation of parallel acting transcriptional programs. Consequently, components of these circuits define new therapeutic opportunities that may help to curb melanoma metastasis.

PMID:
27580028
PMCID:
PMC5161587
DOI:
10.1038/nature19347
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors disclose no potential conflicts of interest. Author Information The authors declare no competing financial interests. Readers are welcome to comment on the online version of the paper.

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