title: TRIM16 inhibits proliferation and migration through regulation of interferon beta 1 in melanoma cells.
abstract: High basal or induced expression of the tripartite motif protein, TRIM16, leads to reduce cell growth and migration of neuroblastoma and skin squamous cell carcinoma cells. However, the role of TRIM16 in melanoma is currently unknown. TRIM16 protein levels were markedly reduced in human melanoma cell lines, compared with normal human epidermal melanocytes due to both DNA methylation and reduced protein stability. TRIM16 knockdown strongly increased cell migration in normal human epidermal melanocytes, while TRIM16 overexpression reduced cell migration and proliferation of melanoma cells in an interferon beta 1 (IFNβ1)-dependent manner. Chromatin immunoprecipitation assays revealed TRIM16 directly bound the IFNβ1 gene promoter. Low level TRIM16 expression in 91 melanoma patient samples, strongly correlated with lymph node metastasis, and, predicted poor patient prognosis in a separate cohort of 170 melanoma patients with lymph node metastasis. The BRAF inhibitor, vemurafenib, increased TRIM16 protein levels in melanoma cells in vitro, and induced growth arrest in BRAF-mutant melanoma cells in a TRIM16-dependent manner. High levels of TRIM16 in melanoma tissues from patients treated with Vemurafenib correlated with clinical response. Our data, for the first time, demonstrates TRIM16 is a marker of cell migration and metastasis, and a novel treatment target in melanoma.
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia.
authors.forename: Selina K
authors.initials: SK
authors.lastname: Sutton
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Koach
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia.
authors.forename: Owen
authors.initials: O
authors.lastname: Tan
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Carter
authors.affiliation: Melanoma Institute Australia and the University of Sydney, Sydney Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: Wilmott
authors.affiliation: Melanoma Institute Australia and the University of Sydney, Sydney Australia. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney and Discipline of Pathology, Sydney Medical School, The University of Sydney, Australia.
authors.forename: Benafsha
authors.initials: B
authors.lastname: Yosufi
authors.affiliation: Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney and Discipline of Pathology, Sydney Medical School, The University of Sydney, Australia.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Haydu
authors.affiliation: Melanoma Institute Australia and the University of Sydney, Sydney Australia. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney and Discipline of Pathology, Sydney Medical School, The University of Sydney, Australia.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.affiliation: Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney and Discipline of Pathology, Sydney Medical School, The University of Sydney, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.affiliation: Melanoma Institute Australia and the University of Sydney, Sydney Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Molecular Oncology Laboratory, Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Grant
authors.initials: G
authors.lastname: McArthur
authors.affiliation: Priority Research Centre for Cancer Research, Oncology and Immunology Unit, University of Newcastle, NSW, Australia.
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: Melanoma Institute Australia and the University of Sydney, Sydney Australia. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney and Discipline of Pathology, Sydney Medical School, The University of Sydney, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia.
authors.forename: Belamy B
authors.initials: BB
authors.lastname: Cheung
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia. Kids Cancer Centre, Sydney Children's Hospital, Sydney, Australia.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D000077484:Vemurafenib
chemical_list: D004268:DNA-Binding Proteins; D007211:Indoles; D013449:Sulfonamides; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D000077484:Vemurafenib; D016899:Interferon-beta; C117731:TRIM16 protein, human; D044767:Ubiquitin-Protein Ligases