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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Bibliographic Details
Published in:Pigment Cell & Melanoma Research Vol. 32; no. 6; pp. 792 - 808
Main Authors: Louphrasitthiphol, Pakavarin, Ledaki, Ioanna, Chauhan, Jagat, Falletta, Paola, Siddaway, Robert, Buffa, Francesca M., Mole, David R., Soga, Tomoyoshi, Goding, Colin R.
Format: Journal Article
Language:English
Published: England Wiley 01.11.2019
Wiley Subscription Services, Inc
John Wiley and Sons Inc
Subjects:
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
Online Access:Get full text
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Summary: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.
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ISSN:1755-1471
1755-148X
1755-148X
DOI:10.1111/pcmr.12802