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Hypoxia and MITF control metastatic behaviour in mouse and human melanoma cells

Oncogene volume 31, pages 2461–2470 (2012)Cite this article

Abstract

Melanomas are very aggressive neoplasms with notorious resistance to therapeutics. It was recently proposed that the remarkable phenotypic plasticity of melanoma cells allows for the rapid development of both resistance to chemotherapeutic drugs and invasive properties. Indeed, the capacity of melanoma cells to form distant metastases is the main cause of mortality in melanoma patients. Therefore, the identification of the mechanism controlling melanoma phenotype is of paramount importance. In the present report, we show that deletion of microphthalmia-associated transcription factor (MITF), the master gene in melanocyte differentiation, is sufficient to increase the metastatic potential of mouse and human melanoma cells. MITF silencing also increases fibronectin and Snail, two mesenchymal markers that might explain the increased invasiveness in vitro and in vivo. Furthermore, ablation of this population by Forskolin-induced differentiation or MITF-forced expression significantly decreases tumour and metastasis formation, suggesting that eradication of low-MITF cells might improve melanoma treatment. Moreover, we demonstrate that a hypoxic microenvironment decreases MITF expression through an indirect, hypoxia-inducible factor 1 (HIF1)α-dependant transcriptional mechanism, and increases the tumourigenic and metastatic properties of melanoma cells. We identified Bhlhb2, a new factor in melanoma biology, as the mediator of hypoxia/HIF1α inhibitory effect on MITF expression. Our results reveal a hypoxia–HIF1α–BHLHB2–MITF cascade controlling the phenotypic plasticity in melanoma cells and favouring metastasis development. Targeting this pathway might be helpful in the design of new anti-melanoma therapies.

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Acknowledgements

We thank Giorgetti-Peraldi Sophie, Regazzetti Claire and Karine Bille for their help. Bhlhb2 reporter plasmid and expression vector were a kind gift from Dr S Egan (Toronto, Canada). This work was supported by the ‘Fondation de France’, and Societé Française de Dermatologie. YC has been supported by ARC's fellowships. The authors greatly acknowledge the C3M Imaging core facility (microscopy and imaging platform Côte d'Azur, MICA) and the C3M animal room facility.

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Authors and Affiliations

  1. INSERM U895, Centre Méditerranéen de Médecine Moléculaire, Equipe 1, Biology and Pathologies of Melanocytes, Equipe Labellisée par la Ligue Contre le Cancer, Nice, France

    Y Cheli, S Giuliano, N Fenouille, M Allegra, P Bahadoran, S Tartare-Deckert, C Bertolotto & R Ballotti

  2. Université de Nice-Sophia Antipolis, UFR médecine, Nice, France

    Y Cheli, S Giuliano, N Fenouille, M Allegra, P Hofman, P Bahadoran, J-P Lacour, S Tartare-Deckert, C Bertolotto & R Ballotti

  3. ERI21/EA 4319 and Human Biobank, Nice, France

    V Hofman & P Hofman

  4. Department of Dermatology, CHU NICE, Nice, France

    P Bahadoran, J-P Lacour, S Tartare-Deckert, C Bertolotto & R Ballotti

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  1. Y Cheli
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  2. S Giuliano
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Correspondence to R Ballotti.

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Cheli, Y., Giuliano, S., Fenouille, N. et al. Hypoxia and MITF control metastatic behaviour in mouse and human melanoma cells. Oncogene 31, 2461–2470 (2012). https://doi.org/10.1038/onc.2011.425

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  • DOI: https://doi.org/10.1038/onc.2011.425

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