Super-enhancers define a proliferative PGC-1[alpha]-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]...

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Published inOncogene Vol. 37; no. 4; p. 512
Main Authors Gelato, K A, Schöckel, L, Klingbeil, O, Rückert, T, Lesche, R, Toedling, J, Kalfon, E, Héroult, M, Lejeune, P, Mönning, U, Fernández-Montalván, A E, Bäurle, S, Siegel, S, Haendler, B
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group 25.01.2018
Subjects
Care and treatment
Development and progression
Electron transport
Enhancers
Epigenetics
Gene expression
Genetic aspects
Health aspects
Melanoma
Mitochondria
Oxidative phosphorylation
Phenotypes
Phosphorylation
Regulatory sequences
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Summary: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 BRD4 was 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. Oncogene (2018) 37, 512-521; doi: 10.1038/onc.2017.325; published online 9 October 2017
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2017.325