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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-10, Vol.108 (43), p.17587-17588
• Main Authors: Feige, Erez, Yokoyama, Satoru, Levy, Carmit, Khaled, Mehdi, Igras, Vivien, Lin, Richard J., Lee, Stephen, Widlund, Hans R., Granter, Scott R., Kung, Andrew L., Fisher, David E.
• Format: Article
• Language: English
• Subjects: anaerobic conditions; Analysis of Variance; Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological Sciences; Blotting, Western; Cell growth; Cell Hypoxia - physiology; Cell survival; Chondrocytes; Chromatin Immunoprecipitation; Clear cells; DNA Primers - genetics; Fluorescent Antibody Technique; gene expression regulation; Gene Expression Regulation - physiology; Gene silencing; Homeodomain Proteins - metabolism; Humans; Hypoxia; Hypoxia-Inducible Factor 1 - metabolism; Immunohistochemistry; Melanocytes; Melanocytes - metabolism; Melanoma; Melanoma - metabolism; Metastases; Metastasis; Mice; Mice, Nude; Microphthalmia-associated transcription factor; Microphthalmia-Associated Transcription Factor - metabolism; Molecules; Oncogenes; Pigments; Plasmids - genetics; PNAS Plus; PNAS PLUS (AUTHOR SUMMARIES); procollagen-proline dioxygenase; prolyl hydroxylase; Promoters; Proteins; Real-Time Polymerase Chain Reaction; Repressors; RNA Interference; Rodents; Sarcoma; transcription (genetics); transcription factors; Xenografts
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1106351108

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 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.