title: Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor.
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.
authors: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia.
authors: T M
authors: TM
authors: Becker
authors: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia.
authors: S C
authors: SC
authors: Boyd
authors: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia.
authors: B
authors: B
authors: Mijatov
authors: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia.
authors: K
authors: K
authors: Gowrishankar
authors: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia.
authors: S
authors: S
authors: Snoyman
authors: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia.
authors: G M
authors: GM
authors: Pupo
authors: Melanoma Institute Australia, Sydney, New South Wales, Australia.
authors: R A
authors: RA
authors: Scolyer
authors: 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.
authors: G J
authors: GJ
authors: Mann
authors: 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.
authors: R F
authors: RF
authors: Kefford
authors: Immunology and Oncology Unit, University of Newcastle, Newcastle, New South Wales, Australia.
authors: X D
authors: XD
authors: Zhang
authors: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia.
authors: H
authors: H
authors: Rizos
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf