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

T. M. Becker*, S. C. Boyd, B. Mijatov, K. Gowrishankar, S. Snoyman, G. M. Pupo, R. A. Scolyer, G. J. Mann, R. F. Kefford, X. D. Zhang, H. Rizos

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1158-1166
Number of pages9
JournalOncogene
Volume33
Issue number9
DOIs
Publication statusPublished - 27 Feb 2014
Externally publishedYes

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