title: High TDP43 expression is required for TRIM16-induced inhibition of cancer cell growth and correlated with good prognosis of neuroblastoma and breast cancer patients.
abstract: Tripartite Motif-containing protein 16 (TRIM16) is a member of a large family of tripartite motif (TRIM) proteins, that has been implicated in the pathogenesis of multiple cancers. However, the mechanism by which TRIM16 acts as a tumour suppressor is currently unknown. We used the versatile yeast two-hybrid assay on a cDNA library from human testes, which has relative high TRIM16 expression, to identify potential TRIM16-binding proteins. We identified transactive response DNA-binding protein 43 (TDP43) as a novel TRIM16 binding protein. Co-immunoprecipitation assay demonstrated that TDP43 bound TRIM16 in neuroblastoma and breast cancer cells. Enforced over-expression of TRIM16 increased the protein half-life of TDP43, through the inhibition of the proteosomal degradation pathway. High levels of TRIM16 and TDP43 are associated with good prognosis in both human neuroblastoma and breast cancer tissues. Importantly, we found TDP43 expression was required for TRIM16-induced inhibition of neuroblastoma and breast cancer cell growth and the repressive effect of TRIM16 on cell cycle regulatory proteins, E2F1 and pRb. Taken together, our data suggest that TRIM16 and TDP43 are both good prognosis indicators; also we showed that TRIM16 inhibits cancer cell viability by a novel mechanism involving interaction and stabilisation of TDP43 with consequent effects on E2F1 and pRb proteins.
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Sydney, Australia.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Kim
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Sydney, Australia.
authors.forename: Owen
authors.initials: O
authors.lastname: Tan
authors.affiliation: Kids Cancer Centre, Sydney Children's Hospital, Randwick 2031, Sydney, Australia.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Sydney, Australia; Kids Cancer Centre, Sydney Children's Hospital, Randwick 2031, Sydney, Australia.
authors.forename: Toby
authors.initials: T
authors.lastname: Trahair
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Sydney, Australia.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Sydney, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Sydney, Australia.
authors.forename: Murray D
authors.initials: MD
authors.lastname: Norris
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Sydney, Australia; Kids Cancer Centre, Sydney Children's Hospital, Randwick 2031, Sydney, Australia. Electronic address: g.marshall@unsw.edu.au.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Sydney, Australia. Electronic address: bcheung@ccia.unsw.edu.au.
authors.forename: Belamy B
authors.initials: BB
authors.lastname: Cheung
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004247:DNA / Q000008:administration & dosage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D016160:Retinoblastoma Protein / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
chemical_list: D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D016160:Retinoblastoma Protein; C000598624:TARDBP protein, human; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D004247:DNA; C117731:TRIM16 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Breast cancer; Neuroblastoma; TDP43; TRIM16; Yeast two-hybrid assay