Metabolic changes are linked to epigenetic reprogramming and play important 
roles in several tumor types. PGC-1α is a transcriptional coactivator 
controlling mitochondrial biogenesis and is linked to oxidative phosphorylation. 
We provide evidence that melanoma models with elevated PGC-1α 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 BRD4 was identified for the PGC-1α 
gene. BET inhibitor treatment prevented this interaction, leading to a dramatic 
reduction of PGC-1α expression. Accordingly, BET inhibition diminished 
respiration and mitochondrial function in cells. In vivo, melanoma models with 
high PGC-1α expression strongly responded to BET inhibition by reduction of 
PGC-1α 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.