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Hypoxia-induced transcriptional repression of the melanoma-associated oncogene MITF.


ABSTRACT: Microphthalmia-associated transcription factor (MITF) regulates normal melanocyte development and is also a lineage-selective oncogene implicated in melanoma and clear-cell sarcoma (i.e., melanoma of soft parts). We have observed that MITF expression is potently reduced under hypoxic conditions in primary melanocytes and melanoma and clear cell sarcoma cells through hypoxia inducible factor 1 (HIF1)-mediated induction of the transcriptional repressor differentially expressed in chondrocytes protein 1 (DEC1) (BHLHE40), which subsequently binds and suppresses the promoter of M-MITF (melanocyte-restricted MITF isoform). Correspondingly, hypoxic conditions or HIF1? stabilization achieved by using small-molecule prolyl-hydroxylase inhibitors reduced M-MITF expression, leading to melanoma cell growth arrest that was rescued by ectopic expression of M-MITF in vitro. Prolyl hydroxylase inhibition also potently suppressed melanoma growth in a mouse xenograft model. These studies illuminate a physiologic hypoxia response in pigment cells leading to M-MITF suppression, one that suggests a potential survival advantage mechanism for MITF amplification in metastatic melanoma and offers a small-molecule strategy for suppression of the MITF oncogene in vivo.

SUBMITTER: Feige E 

PROVIDER: S-EPMC3203758 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Hypoxia-induced transcriptional repression of the melanoma-associated oncogene MITF.

Feige Erez E   Yokoyama Satoru S   Levy Carmit C   Khaled Mehdi M   Igras Vivien V   Lin Richard J RJ   Lee Stephen S   Widlund Hans R HR   Granter Scott R SR   Kung Andrew L AL   Fisher David E DE  

Proceedings of the National Academy of Sciences of the United States of America 20110926 43


Microphthalmia-associated transcription factor (MITF) regulates normal melanocyte development and is also a lineage-selective oncogene implicated in melanoma and clear-cell sarcoma (i.e., melanoma of soft parts). We have observed that MITF expression is potently reduced under hypoxic conditions in primary melanocytes and melanoma and clear cell sarcoma cells through hypoxia inducible factor 1 (HIF1)-mediated induction of the transcriptional repressor differentially expressed in chondrocytes prot  ...[more]

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