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Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor

Oncogene volume 33, pages 1158–1166 (2014)Cite this article

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Abstract

Approximately 50% of melanomas depend on mutant B-RAF for proliferation, metastasis and survival. The inhibition of oncogenic B-RAF with highly targeted compounds has produced remarkable albeit short-lived clinical responses in B-RAF mutant melanoma patients. Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors, and the identification of B-RAF targets may provide new strategies for managing melanoma. Oncogenic B-RAFV600E is known to promote the stabilizing phosphorylation of the anti-apoptotic protein Mcl-1, implicated in melanoma survival and chemoresistance. We now show that B-RAFV600E signaling also induces the transcription of Mcl-1 in melanocytes and melanoma. We demonstrate that activation of STAT3 serine-727 and tyrosine-705 phosphorylations is promoted by B-RAFV600E activity and that the Mcl-1 promoter is dependent on a STAT consensus-site for B-RAF-mediated activation. Consequently, suppression of STAT3 activity disrupted B-RAFV600E-mediated induction of Mcl-1 and reduced melanoma cell survival. We propose that STAT3 has a central role in the survival and contributes to chemoresistance of B-RAFV600E melanoma.

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Acknowledgements

This work is supported by the Program Grant 633004 and project grants of the National Health and Medical Research Council of Australia (NHMRC), Translational Research Program Grant 10/TPG/1-02 of the Cancer Institute New South Wales and an infrastructure grant to Westmead Millennium Institute by the Health Department of NSW through Sydney West Area Health Service. Westmead Institute for Cancer Research is the recipient of capital grant funding from the Australian Cancer Research Foundation. HR is a recipient of a Cancer Institute New South Wales, Research Fellowship and a NHMRC Senior Research Fellowship. RAS is a recipient of a Cancer Institute New South Wales, Research Fellowship.

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Authors and Affiliations

  1. Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia

    T M Becker, S C Boyd, B Mijatov, K Gowrishankar, S Snoyman, G M Pupo, G J Mann, R F Kefford & H Rizos

  2. Melanoma Institute Australia, Sydney, New South Wales, Australia

    R A Scolyer, G J Mann & R F Kefford

  3. Immunology and Oncology Unit, University of Newcastle, Newcastle, New South Wales, Australia

    X D Zhang

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  1. T M Becker
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Becker, T., Boyd, S., Mijatov, B. et al. Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor. Oncogene 33, 1158–1166 (2014). https://doi.org/10.1038/onc.2013.45

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