Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Qld, Australia.
Carcinogenesis. 2013 Apr;34(4):750-9. doi: 10.1093/carcin/bgs391. Epub 2012 Dec 13.
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.
哺乳动物细胞的有丝分裂进程受到 E3 泛素连接酶有丝分裂促进复合物（APC）/C 的严格调控。APC/C 的失调在癌细胞中经常观察到，被认为有助于染色体不稳定和癌症易感性。在这项研究中，我们鉴定了 Daxx 作为一种新型 APC/C 抑制剂，在前列腺癌中经常过表达。Daxx 在体内与 APC/C 共激活因子 Cdc20 和 Cdh1 相互作用，Cdc20 的结合依赖于 Daxx 蛋白 N 端附近的共识破坏盒。Daxx 的异位表达，但不是 D 盒缺失突变体（DaxxΔD-box），抑制了 APC/Cdc20 和 APC/Cdh1 底物的降解，导致有丝分裂进程的短暂延迟。Daxx 在前列腺癌组织中经常上调；表达水平与 Gleason 评分和疾病转移呈正相关（分别为 P = 0.027 和 0.032）。此外，在非恶性前列腺上皮细胞系中异位表达 Daxx 在有丝分裂应激下诱导了多倍体。我们的数据表明，Daxx 可能作为一种新型的 APC/C 抑制剂发挥作用，促进前列腺癌发展过程中的染色体不稳定。
