title: JRK is a positive regulator of β-catenin transcriptional activity commonly overexpressed in colon, breast and ovarian cancer.
abstract: The loss of β-catenin inhibitory components is a well-established mechanism of carcinogenesis but β-catenin hyperactivity can also be enhanced through its coactivators. Here we first interrogated a highly validated genomic screen and the largest repository of cancer genomics data and identified JRK as a potential new oncogene and therapeutic target of the β-catenin pathway. We proceeded to validate the oncogenic role of JRK in colon cancer cells and primary tumors. Consistent with a β-catenin activator function, depletion of JRK in several cancer cell lines repressed β-catenin transcriptional activity and reduced cell proliferation. Importantly, JRK expression was aberrantly elevated in 21% of colorectal cancers, 15% of breast and ovarian cancers and was associated with increased expression of β-catenin target genes and increased cell proliferation. This study shows that JRK is required for β-catenin hyperactivity regardless of the adenomatous polyposis coli/β-catenin mutation status and targeting JRK presents new opportunities for therapeutic intervention in cancer.
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.|St Vincent's Clinical School, UNSW Medicine, UNSW Australia, Sydney, New South Wales, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Pangon
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
authors.forename: I
authors.initials: I
authors.lastname: Ng
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Giry-Laterriere
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Currey
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Morgan
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.|St Vincent's Clinical School, UNSW Medicine, UNSW Australia, Sydney, New South Wales, Australia.
authors.forename: F
authors.initials: F
authors.lastname: Benthani
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
authors.forename: P N
authors.initials: PN
authors.lastname: Tran
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Al-Sohaily
authors.affiliation: St Vincent's Clinical School, UNSW Medicine, UNSW Australia, Sydney, New South Wales, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Segelov
authors.affiliation: Biological Mass Spectrometry Unit, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.|Charles Perkins Centre, School of Molecular Bioscience, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: B L
authors.initials: BL
authors.lastname: Parker
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.|St Vincent's Clinical School, UNSW Medicine, UNSW Australia, Sydney, New South Wales, Australia.|Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Cowley
authors.affiliation: Cytogenetics, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
authors.forename: D C
authors.initials: DC
authors.lastname: Wright
authors.affiliation: Cytogenetics, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
authors.forename: L
authors.initials: L
authors.lastname: St Heaps
authors.affiliation: Cytogenetics, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Carey
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.|St Vincent's Clinical School, UNSW Medicine, UNSW Australia, Sydney, New South Wales, Australia.
authors.forename: I
authors.initials: I
authors.lastname: Rooman
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.|St Vincent's Clinical School, UNSW Medicine, UNSW Australia, Sydney, New South Wales, Australia.
authors.forename: M R J
authors.initials: MR
authors.lastname: Kohonen-Corish
mesh_terms: D021581:Active Transport, Cell Nucleus; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D003198:Computer Simulation; D004268:DNA-Binding Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D000072417:Protein Domains; D016601:RNA-Binding Proteins; D014158:Transcription, Genetic; D015854:Up-Regulation; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C113872:JRK protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D051176:beta Catenin