Letter | Published:

A PGC1α-mediated transcriptional axis suppresses melanoma metastasis

Nature volume 537, pages 422426 (15 September 2016) | Download Citation

Abstract

Melanoma is the deadliest form of commonly encountered skin cancer because of its rapid progression towards metastasis1,2. 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 stress3 and reprograms melanoma metabolism to influence drug sensitivity and survival4,5. 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 metastasis6,7,8. Inhibition of BRAFV600E using vemurafenib9, 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.

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Acknowledgements

We thank R. Bronson for his critical analysis of the mouse histology, the Nikon Imaging Center at Harvard Medical School for help with light microscopy and members of the Puigserver laboratory for discussions. J.-H.L was supported in part by a postdoctoral fellowship from the American Heart Association (13POST14750008) and the National Research Foundation from the South-Korean government (2015R1A2A2A01002483). These studies were funded in part by the Claudia Adams Barr Program in Cancer Research (to P.P.), Dana-Farber Cancer Institute internal funds (to P.P.) and NIH R01CA181217 (to P.P.), as well as the Friends of Dana-Farber Award (to C.L.).

Author information

Author notes

    • Ji-Hong Lim

    Present address: Department of Biomedical Chemistry, College of Biomedical and Health Science, Konkuk University, Chungbuk, Chungju, Chungcheongbuk-do 380-701, South Korea.

    • Chi Luo
    •  & Ji-Hong Lim

    These authors contributed equally to this work.

Affiliations

  1. Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Chi Luo
    • , Ji-Hong Lim
    • , Yoonjin Lee
    • , Ajith Thomas
    • , Francisca Vazquez
    •  & Pere Puigserver
  2. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    • Yoonjin Lee
  3. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Scott R. Granter
  4. Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA

    • Francisca Vazquez
  5. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Francisca Vazquez
  6. Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Hans R. Widlund

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Contributions

P.P. and F.V. conceived the project. C.L. contributed to immunoblots for Figs 1d, 2a, 3h, 4d,4c and Extended Data Figs 2g, 5e, 5i, 6a, 7c, 8d and 8f; qPCR for Figs 2, 3j, Extended Data Figs 2g, 4, 5e, 5i, and 8b; in vitro migration for Fig. 2c, Extended Data Figs 2h, 2i; in vivo experiments for Figs 1g 1h 2, and Extended Data Fig. 3. J.-H.L. contributed to all the other western blots, qPCR for Figs 1, 3 and 4, Extended Data Figs 2, 5, 6, 7, 8, and 9; all the in vitro migration and invasion experiments except Fig. 2c, Extended Data Figs 2h, 2i; all the in vivo experiments except Figs 1g, 1h, 2, and Extended Data Fig. 3. Y.L. contributed to all in vivo experiments and edited the manuscript. A.T. contributed to immunoblotting experiments for Figs 1d, 2a, 3h, 4d and 4c. F.V. and H.R.W. designed and performed the bioinformatic analyses for Extended Data Figs 1, 8g, and Fig. 1a and 1c, respectively. S.R.G. performed immunohistochemistry experiments. P.P., F.V., J.-H.L., H.R.W. and C.L. prepared the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Pere Puigserver.

Reviewer Information

Nature thanks G. Bollag and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

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  1. 1.

    Supplementary Information

    This file contains the uncropped blots for Figures 1d, 2b, 3h, 4c, 4d, and Extended Data Figures 2g, 3c, 5a, 5e, 5h, 5i, 6a, 6b, 6d, 7c, 8c, 8d, 8f.

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DOI

https://doi.org/10.1038/nature19347

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