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

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

SUBMITTER: Gelato KA 

PROVIDER: S-EPMC5799712 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature