Abstract
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.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Azepines / pharmacology
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Azepines / therapeutic use
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Benzodiazepines / pharmacology
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Benzodiazepines / therapeutic use
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Cell Cycle Proteins
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Drug Resistance, Neoplasm / genetics
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Enhancer Elements, Genetic / genetics*
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Epigenesis, Genetic
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Female
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Humans
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Melanoma / drug therapy
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Melanoma / genetics*
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Melanoma / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Nude
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Mitochondria / drug effects
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Mitochondria / metabolism
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / metabolism
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Patient Selection
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics*
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
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Protein Binding / genetics
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SOXE Transcription Factors / genetics
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SOXE Transcription Factors / metabolism
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Skin Neoplasms / drug therapy
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Skin Neoplasms / genetics
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Skin Neoplasms / pathology
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / metabolism
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Treatment Outcome
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Triazoles / pharmacology
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Triazoles / therapeutic use
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Xenograft Model Antitumor Assays
Substances
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(+)-JQ1 compound
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Antineoplastic Agents
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Azepines
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BAY 1238097
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BRD4 protein, human
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Cell Cycle Proteins
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Nuclear Proteins
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PPARGC1A protein, human
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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SOX10 protein, human
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SOXE Transcription Factors
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Transcription Factors
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Triazoles
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Benzodiazepines