MITF controls the TCA cycle to modulate the melanoma hypoxia response

In response to the dynamic intra‐tumor microenvironment, melanoma cells adopt distinct phenotypic states associated with differential expression of the microphthalmia‐associated transcription factor (MITF). The response to hypoxia is driven by hypoxia‐inducible transcription factors (HIFs) that repr...

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Veröffentlicht in:	Pigment Cell & Melanoma Research Jg. 32; H. 6; S. 792 - 808
Hauptverfasser:	Louphrasitthiphol, Pakavarin, Ledaki, Ioanna, Chauhan, Jagat, Falletta, Paola, Siddaway, Robert, Buffa, Francesca M., Mole, David R., Soga, Tomoyoshi, Goding, Colin R.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	England Wiley 01.11.2019 Wiley Subscription Services, Inc John Wiley and Sons Inc
Schlagworte:	Angiogenesis Biotechnology Cell Line, Tumor Citric Acid Cycle Deoxyribonucleic acid DNA Gene expression Gene Expression Regulation, Neoplastic Genes Genome, Human genomewide glucose limitation Humans Hypoxia Hypoxia-Inducible Factor 1, alpha Subunit Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Melanoma Melanoma - genetics Melanoma - pathology Metabolism Microphthalmia-Associated Transcription Factor Microphthalmia-Associated Transcription Factor - metabolism MITF Neoplasm Invasiveness Original Original Articles Succinate Dehydrogenase Succinate Dehydrogenase - metabolism Transcription factors transcription factors, TCA cycle, hypoxia, genomewide, glucose limitation, hypoxia, melanoma, MITF Tricarboxylic acid cycle Tumor Hypoxia Tumor Hypoxia - genetics Up-Regulation Up-Regulation - genetics hypoxia melanoma genomewide glucose limitation MITF
ISSN:	1755-1471, 1755-148X, 1755-148X
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Zusammenfassung:	In response to the dynamic intra‐tumor microenvironment, melanoma cells adopt distinct phenotypic states associated with differential expression of the microphthalmia‐associated transcription factor (MITF). The response to hypoxia is driven by hypoxia‐inducible transcription factors (HIFs) that reprogram metabolism and promote angiogenesis. HIF1α indirectly represses MITF that can activate HIF1α expression. Although HIF and MITF share a highly related DNA‐binding specificity, it is unclear whether they co‐regulate subset of target genes. Moreover, the genomewide impact of hypoxia on melanoma and whether melanoma cell lines representing different phenotypic states exhibit distinct hypoxic responses is unknown. Here we show that three different melanoma cell lines exhibit widely different hypoxia responses with only a core 23 genes regulated in common after 12 hr in hypoxia. Surprisingly, under hypoxia MITF is transiently up‐regulated by HIF1α and co‐regulates a subset of HIF targets including VEGFA. Significantly, we also show that MITF represses itself and also regulates SDHB to control the TCA cycle and suppress pseudo‐hypoxia. Our results reveal a previously unsuspected role for MITF in metabolism and the network of factors underpinning the hypoxic response in melanoma.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1755-1471 1755-148X 1755-148X
DOI:	10.1111/pcmr.12802