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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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.).
Extended data figures
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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N6-methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO-PGC-1α signalling axis
Journal of Cellular and Molecular Medicine (2019)