br colorectal pancreatic and prostate
colorectal , pancreatic  and prostate cancers [13–17]. It is also associated with aggressive proliferation and metastasis of cancers [42,43]. We assessed the expression level of CDC20 in spheroid, CD44+ or chemo-resistant cells. The results supported that CDC20 pro-motes the development of prostate cancer by regulating the prostate CSCs, targeting CDC20 in CD44+ prostate CSCs impeded their stemness and attenuated their ability to tumorigenesis in vivo.
To uncover the underlying mechanisms how CDC20 regulates pros-tate CSC stemness, RNA sequences were performed to screen the differ-entially regulated genes and corresponding pathways under
knockdown of CDC20 in CD44+ C4–2B prostate cancer cells. Interest-ingly, the pathway of transcriptional regulation of pluripotent stem 131060-14-5 was significantly affected in the Lv-shCDC20 group, as well as a se-ries of pathways consistently down-regulated, such as the β-catenin/ TCF transactivation complex, the Hippo pathway, the Notch pathway and the ABC family, which were involved in the regulation of biological functions and characteristics of stem-like cells and drug resistance in previous study . Among them, abnormal activation of the Wnt/β-catenin signaling pathway usually exerts a critical role in regulating prostate CSCs expansion during prostate cancer progression and
androgen deprivation treatment resistance [45,46]. Our data found that down-regulation of CDC20 inhibits mRNA expression of c-Jun, c-Myc, MMP7, cyclin D1 and TCF4, which are the major downstream targets for β-catenin/TCF signaling, and the MMP7 expression was weaken may give a clue for illuminating its role on impeding the invasion ability of cancer stem-like cells. It is well known that β-catenin is always phos-phorylated in cytoplasm by its “destructive complex” and sequentially degraded by the proteasome system . Thus, disrupting the forma-tion of this complex can result in the accumulation of stabilised β-catenin and its translocation into nucleus to transactive the down-stream genes such as MMP7 and c-Myc. To elucidate how CDC20 affects the Wnt/β-catenin pathway, we found that CDC20-driven regulation on β-catenin signaling by promoting Axin1 degradation. Thus, the inactiva-tion of destructive complexes stabilised β-catenin and enhanced its nu-clear translocation and transactive ability in prostate CSCs. Previous study suggested that c-Myc, the key target effector of β-catenin path-way, is closely related to stem-like properties regulation, whereas de-pletion of c-Myc could reverse the tumourigenic potential of CSCs . CDC20 is an important target gene for c-Myc , therefore, whether a positive feedback loop could be formed between CDC20 and c-Myc still needs to be further elucidated.
Based on our results, we believe that CDC20, through its regulation of prostate CSCs, contributes at least to some extent to the aggressive-ness and chemo-resistance of prostate cancer, which was further sup-ported by clinical studies showing that CDC20 in combination with CD44 or β-catenin provides a new prognostic indicator for prostate can-cer patients. In conclusion, knockdown of CDC20 can be used for thera-peutic benefit and represents an effective adjuvant anti-cancer treatment to eliminate CSCs during prostate cancer progression.
Funding sources and acknowledgement
Declaration of interests
The authors declare no conflict of interest in this study.
Qin Zhang, Hai Huang contributed to study concept, design and ac-quisition of data. Hai Huang and Qin Zhang contributed to drafting of the manuscript. Qin Zhang, Hai Huang, Jiang Li, Chunying Liu and Bin Sun contributed to acquisition of data. Lu Chen and Ao Liu contributed to analysis and interpretation of data. Lu Chen and Jiang Li contributed to statistical analysis. Changqing Su, Danfeng Xu and Yi Gao contributed to critical revision of the manuscript.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
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