title: Daxx regulates mitotic progression and prostate cancer predisposition.
abstract: Mitotic progression of mammalian cells is tightly regulated by the E3 ubiquitin ligase anaphase promoting complex (APC)/C. Deregulation of APC/C is frequently observed in cancer cells and is suggested to contribute to chromosome instability and cancer predisposition. In this study, we identified Daxx as a novel APC/C inhibitor frequently overexpressed in prostate cancer. Daxx interacts with the APC/C coactivators Cdc20 and Cdh1 in vivo, with the binding of Cdc20 dependent on the consensus destruction boxes near the N-terminal of the Daxx protein. Ectopic expression of Daxx, but not the D-box deleted mutant (DaxxΔD-box), inhibited the degradation of APC/Cdc20 and APC/Cdh1 substrates, leading to a transient delay in mitotic progression. Daxx is frequently upregulated in prostate cancer tissues; the expression level positively correlated with the Gleason score and disease metastasis (P = 0.027 and 0.032, respectively). Furthermore, ectopic expression of Daxx in a non-malignant prostate epithelial cell line induced polyploidy under mitotic stress. Our data suggest that Daxx may function as a novel APC/C inhibitor, which promotes chromosome instability during prostate cancer development.
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Qld, Australia.
authors.forename: Pak Shing
authors.initials: PS
authors.lastname: Kwan
authors.forename: Chi Chiu
authors.initials: CC
authors.lastname: Lau
authors.forename: Yung Tuen
authors.initials: YT
authors.lastname: Chiu
authors.forename: Cornelia
authors.initials: C
authors.lastname: Man
authors.forename: Ji
authors.initials: J
authors.lastname: Liu
authors.forename: Kai Dun
authors.initials: KD
authors.lastname: Tang
authors.forename: Yong Chuan
authors.initials: YC
authors.lastname: Wong
authors.forename: Ming-Tat
authors.initials: MT
authors.lastname: Ling
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D025601:Adenomatous Polyposis Coli Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D064199:Cdc20 Proteins; D002453:Cell Cycle; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D056970:Co-Repressor Proteins; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008938:Mitosis; D018832:Molecular Chaperones; D009154:Mutation; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: C555337:APC protein, human; D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C577488:CDC20 protein, human