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Oncogene. 2014 Feb 27;33(9):1158-66. doi: 10.1038/onc.2013.45. Epub 2013 Mar 4.

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

Author information

1
Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia.
2
Melanoma Institute Australia, Sydney, New South Wales, Australia.
3
1] Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia [2] Melanoma Institute Australia, Sydney, New South Wales, Australia.
4
Immunology and Oncology Unit, University of Newcastle, Newcastle, New South Wales, Australia.

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-RAF(V600E) 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-RAF(V600E) 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-RAF(V600E) 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-RAF(V600E)-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-RAF(V600E) melanoma.

PMID:
23455323
DOI:
10.1038/onc.2013.45
[Indexed for MEDLINE]

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