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MITF controls the TCA cycle to modulate the melanoma hypoxia response.

Abstract

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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  • Authors+Show Affiliations

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    Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

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    Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

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    Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

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    Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

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    Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

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    Department of Oncology, University of Oxford, Oxford, UK.

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    Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

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    Institute for Advanced Biosciences, Keio University, Yamagata, Japan.

    Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

    Source

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31207090

    Citation

    Louphrasitthiphol, Pakavarin, et al. "MITF Controls the TCA Cycle to Modulate the Melanoma Hypoxia Response." Pigment Cell & Melanoma Research, 2019.
    Louphrasitthiphol P, Ledaki I, Chauhan J, et al. MITF controls the TCA cycle to modulate the melanoma hypoxia response. Pigment Cell Melanoma Res. 2019.
    Louphrasitthiphol, P., Ledaki, I., Chauhan, J., Falletta, P., Siddaway, R., Buffa, F. M., ... Goding, C. R. (2019). MITF controls the TCA cycle to modulate the melanoma hypoxia response. Pigment Cell & Melanoma Research, doi:10.1111/pcmr.12802.
    Louphrasitthiphol P, et al. MITF Controls the TCA Cycle to Modulate the Melanoma Hypoxia Response. Pigment Cell Melanoma Res. 2019 Jun 17; PubMed PMID: 31207090.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - MITF controls the TCA cycle to modulate the melanoma hypoxia response. AU - Louphrasitthiphol,Pakavarin, AU - Ledaki,Ioanna, AU - Chauhan,Jagat, AU - Falletta,Paola, AU - Siddaway,Robert, AU - Buffa,Francesca M, AU - Mole,David R, AU - Soga,Tomoyoshi, AU - Goding,Colin R, Y1 - 2019/06/17/ PY - 2019/02/22/received PY - 2019/05/29/revised PY - 2019/06/11/accepted PY - 2019/6/18/pubmed PY - 2019/6/18/medline PY - 2019/6/18/entrez KW - MITF KW - genomewide KW - glucose limitation KW - hypoxia KW - melanoma JF - Pigment cell & melanoma research JO - Pigment Cell Melanoma Res N2 - 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. SN - 1755-148X UR - https://www.unboundmedicine.com/medline/citation/31207090/MITF_controls_the_TCA_cycle_to_modulate_the_melanoma_hypoxia_response L2 - https://doi.org/10.1111/pcmr.12802 DB - PRIME DP - Unbound Medicine ER -