CDT1 facilitates metastasis in prostate cancer and correlates with cell cycle regulation

Article type: Research Article

Authors: Wang, Chunhui^{a; b; 1} | Che, Jizhong^{c; 1} | Jiang, Ying^{d; 1} | Chen, Ping^e | Bao, Guochang^{a; b} | Li, Chunsheng^{a; b; *}

Affiliations: [a] Departments of Urology, Affiliated Hospital of Chifeng University, Chifeng, Inner Mongolia, China | [b] Urology Research Center, Chifeng University, Chifeng, Inner Mongolia, China | [c] Departments of Urology, Yan Tai Affiliated Hospital of Bin Zhou Medical University, Binzhou, Shandong, China | [d] Medical Reproductive Center, Affiliated Hospital of Chifeng University, Chifeng, Inner Mongolia, China | [e] Physical Examination Center, Affiliated Hospital of Chifeng University, Chifeng, Inner Mongolia, China

Correspondence: [*] Corresponding author: Chunsheng Li, Departments of Urology, Affiliated Hospital of Chifeng %****␣cbm-34-cbm210389_temp.tex␣Line␣100␣**** University, No. 42 Wangfu Street, Chifeng, Inner Mongolia 024000, China. Tel.: +86 15004765949; E-mail: 18147637878@163.com.

Note: [1] Equal contributors.

Abstract: BACKGROUND: CDT1 is the essential regulator of the initiation of DNA replication. Overexpressed CDT1 can cause DNA damage through re-replication. However, the function of CDT1 in prostate cancer (PCa) development has not been established. METHODS: Through bioinformatics, expression levels of CDT1 were found to be higher in metastatic PCa when compared to primary PCa. Then, immunohistochemical staining confirmed that the expression of CDT1 was significantly correlated with the occurrence of distant metastasis. For PCa cells, we established a stable clones knockdown CDT1. MTT was used in analyzing the proliferation ability of cells. Migration as well as invasion assays were performed. Effects of CDT1 knockdown on the cell cycle were evaluated by flow cytometry. Expression levels of EMT-associated markers in PCa cells were determined by Western blotting. And PI3K/AKT/GSK3β, a signaling molecule recognized in PCa that can regulate EMT, was detected in protein level. RESULTS: Over expression of CDT1 in PCa cells enhanced cell migration, invasion, tumor metastasis and was correlated with cell cycle regulation. Our results showed that knockdown of CDT1 inhibited G1 to S phase transition and induced the G1 phase cell cycle arrest in PCa cells. Moreover, it upregulated the expressions of epithelial markers (E-cadherin) and down-regulated mesenchymal markers (including Slug, N-cadherin, MMP2, vimentin, Snail, and MMP9) via regulating the phosphorylation level of PI3K, AKT and GSK3β. CONCLUSIONS: CDT1 promotes PCa cell metastasis by promoting cell cycle and PI3K/AKT/GSK3β mediated epithelial-mesenchymal transition (EMT) progression and may be a therapeutic target for metastatic PCa.

Keywords: CDT1, cell cycle, EMT, metastasis, prostate cancer

DOI: 10.3233/CBM-210389

Journal: Cancer Biomarkers, vol. 34, no. 3, pp. 459-469, 2022