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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

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

Gelato K A KA Schöckel L L Klingbeil O O Rückert T T Lesche R R Toedling J J Kalfon E E Héroult M M Lejeune P P Mönning U U Fernández-Montalván A E AE Bäurle S S Siegel S S Haendler B B

Oncogene 20171009 4

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 BRD ...[more]

PMID: 28991225

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Project description:Osteosarcoma (OS) is one of the most common primary malignant tumors of bone in children, which develops from osteoblasts and typically occurs during the rapid growth phase of the bone. Recently, Super-Enhancers(SEs)have been reported to play a crucial role in osteosarcoma growth and metastasis. Therefore, there is an urgent need to identify specific targeted inhibitors of SEs to assist clinical therapy. This study aimed to elucidate the role of BRD4 inhibitor GNE-987 targeting SEs in OS and preliminarily explore its mechanism. We evaluated changes in osteosarcoma cells following treatment with a BRD4 inhibitor GNE-987. We assessed the anti-tumor effect of GNE-987 in vitro and in vivo by Western blot, CCK8, flow cytometry detection, clone formation, xenograft tumor size measurements, and Ki67 immunohistochemical staining, and combined ChIP-seq with RNA-seq techniques to find its anti-tumor mechanism. In this study, we found that extremely low concentrations of GNE-987(2-10 nM) significantly reduced the proliferation and survival of OS cells by degrading BRD4. In addition, we found that GNE-987 markedly induced cell cycle arrest and apoptosis in OS cells. Further study indicated that VHL was critical for GNE-987 to exert its antitumor effect in OS cells. Consistent with in vitro results, GNE-987 administration significantly reduced tumor size in xenograft models with minimal toxicity, and partially degraded the BRD4 protein. KRT80 was identified through analysis of the RNA-seq and ChIP-seq data. U2OS HiC analysis suggested a higher frequency of chromatin interactions near the KRT80 binding site. The enrichment of H3K27ac modification at KRT80 was significantly reduced after GNE-987 treatment. KRT80 was identified as playing an important role in OS occurrence and development. This research revealed that GNE-987 selectively degraded BRD4 and disrupted the transcriptional regulation of oncogenes in OS. GNE-987 has the potential to affect KRT80 against OS.

Dataset Information

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

Publications

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

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