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

Erez Feige, Satoru Yokoyama, Carmit Levy, Mehdi Khaled, Vivien Igras, Richard J. Lin, Stephen Lee, Hans R. Widlund, Scott R. Granter, Andrew L. Kung, David E. Fisher

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

Microphthalmia-associated transcription factor (MITF) regulates normalmelanocyte 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 HIF1α 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.

Original languageEnglish (US)
Pages (from-to)E924-E933
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number43
DOIs
StatePublished - Oct 25 2011

Keywords

  • Cancer
  • Pigmentation
  • Signal transduction

ASJC Scopus subject areas

  • General

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