Daxx regulates mitotic progression and prostate cancer predisposition

Carcinogenesis. 2013 Apr;34(4):750-9. doi: 10.1093/carcin/bgs391. Epub 2012 Dec 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adenomatous Polyposis Coli Protein / antagonists & inhibitors*
  • Adenomatous Polyposis Coli Protein / metabolism
  • Antigens, CD
  • Cadherins / metabolism*
  • Cdc20 Proteins
  • Cell Cycle
  • Cell Cycle Checkpoints
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Chromosomal Instability*
  • Co-Repressor Proteins
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Male
  • Mitosis*
  • Molecular Chaperones
  • Mutation
  • Neoplasm Grading
  • Neoplasm Metastasis
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism*
  • RNA Interference
  • RNA, Small Interfering

Substances

  • APC protein, human
  • Adaptor Proteins, Signal Transducing
  • Adenomatous Polyposis Coli Protein
  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • Cdc20 Proteins
  • Cell Cycle Proteins
  • Co-Repressor Proteins
  • DAXX protein, human
  • Molecular Chaperones
  • Nuclear Proteins
  • RNA, Small Interfering
  • CDC20 protein, human