Super-enhancers define a proliferative PGC-1α-expressing melanoma subgroup sensitive to BET inhibition

Metabolic changes are linked to epigenetic reprogramming and play important roles in several tumor types. PGC-1 alpha is a transcriptional coactivator controlling mitochondrial biogenesis and is linked to oxidative phosphorylation. We provide evidence that melanoma models with elevated PGC-1 alpha levels are characteristic of the proliferative phenotype and are sensitive to bromodomain and extra-terminal domain (BET) inhibitor treatment. A super-enhancer region highly occupied by the BET family member BRD4was identified for the PGC-1 alpha gene. BET inhibitor treatment prevented this interaction, leading to a dramatic reduction of PGC-1 alpha expression. Accordingly, BET inhibition diminished respiration and mitochondrial function in cells. In vivo, melanoma models with high PGC-1 alpha expression strongly responded to BET inhibition by reduction of PGC-1 alpha and impaired tumor growth. Altogether, our findings identify epigenetic regulatory elements that define a subset of melanomas with high sensitivity to BET inhibition, which opens up the opportunity to define melanoma patients most likely to respond to this treatment, depending on their tumor characteristics.