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 BRAF V600E 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.
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