Abstract
Currently, radiotherapy is one of the most attractive treatments for prostate cancer (PCa) patients. However, radioresistance remains a challenging issue and the underlying mechanism is unknown. Growing evidence has demonstrated that CDC20 (Cell division cycle protein 20) plays a pivotal role in a variety of tumors, including PCa. Here, GEPIA database mining and western blot analysis showed that higher expression of CDC20 was observed in PCa tissues and cells. We demonstrated that the expression of CDC20 was increased in PCa cells by irradiation, and knockdown of CDC20 resulted in inhibition of cell proliferation, migration, tumor formation, induced cell apoptosis and increased radiosensitivity in PCa in vitro and in vivo. Furthermore, we observed that CDC20 regulated Twist1 pathway, influencing cell proliferation and migration. These results suggest that targeting CDC20 and Twist1 may be an effective way to improve the radiosensitivity of PCa.
Similar content being viewed by others
Data Availability
The data of this study are available from the corresponding author upon reasonable request.
References
Siegel RL, Miller KD, Wagle NS, Jemal A (2023) Cancer statistics, 2023. CA Cancer J Clin 73:17–48
Allen GW, Howard AR, Jarrard DF, Ritter MA (2007) Management of prostate cancer recurrences after radiation therapy-brachytherapy as a salvage option. Cancer 110:1405–1416
Gay HA, Michalski JM (2018) Radiation Therapy for prostate Cancer. Mo Med 115:146–150
Huang RX, Zhou PK (2020) DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduct Target Ther 5:60
Sun H, Fan G, Deng C, Wu L (2020) miR-4429 sensitized cervical cancer cells to irradiation by targeting RAD51. J Cell Physiol 235:185–193
Wang ZW, Hu X, Ye M, Lin M, Chu M, Shen X (2020) NEDD4 E3 ligase: functions and mechanism in human cancer. Semin Cancer Biol 67:92–101
Liu J, Chen T, Li S, Liu W, Wang P, Shang G (2022) Targeting matrix metalloproteinases by E3 ubiquitin ligases as a way to regulate the tumor microenvironment for cancer therapy. Semin Cancer Biol 86:259–268
Hou B, Chen T, Zhang H, Li J, Wang P, Shang G (2023) The E3 ubiquitin ligases regulate PD-1/PD-L1 protein levels in tumor microenvironment to improve immunotherapy. Front Immunol 14:1123244
Herrmann J, Lerman LO, Lerman A (2007) Ubiquitin and ubiquitin-like proteins in protein regulation. Circ Res 100:1276–1291
He W, Meng J (2023) CDC20: a novel therapeutic target in cancer. Am J Transl Res 15:678–693
Wu F, Sun Y, Chen J et al (2021) The oncogenic role of APC/C activator protein Cdc20 by an Integrated Pan-Cancer Analysis in Human Tumors. Front Oncol 11:721797
Zhang Q, Huang H, Liu A et al (2019) Cell division cycle 20 (CDC20) drives prostate cancer progression via stabilization of beta-catenin in cancer stem-like cells. EBioMedicine 42:397–407
Gayyed MF, El-Maqsoud NM, Tawfiek ER, El Gelany SA, Rahman MF (2016) A comprehensive analysis of CDC20 overexpression in common malignant tumors from multiple organs: its correlation with tumor grade and stage. Tumour Biol 37:749–762
Shang G, Ma X, Lv G (2018) Cell division cycle 20 promotes cell proliferation and invasion and inhibits apoptosis in osteosarcoma cells. Cell Cycle 17:43–52
Wan L, Tan M, Yang J et al (2014) APC(Cdc20) suppresses apoptosis through targeting Bim for ubiquitination and destruction. Dev Cell 29:377–391
Harley ME, Allan LA, Sanderson HS, Clarke PR (2010) Phosphorylation of Mcl-1 by CDK1-cyclin B1 initiates its Cdc20-dependent destruction during mitotic arrest. EMBO J 29:2407–2420
Shirayama M, Toth A, Galova M, Nasmyth K (1999) APC(Cdc20) promotes exit from mitosis by destroying the anaphase inhibitor Pds1 and cyclin Clb5. Nature 402:203–207
van Zon W, Wolthuis RM (2010) Cyclin A and Nek2A: APC/C-Cdc20 substrates invisible to the mitotic spindle checkpoint. Biochem Soc Trans 38:72–77
Wang L, Yang C, Chu M, Wang ZW, Xue B (2021) Cdc20 induces the radioresistance of bladder cancer cells by targeting FoxO1 degradation. Cancer Lett 500:172–181
Banerjee T, Nath S, Roychoudhury S (2009) DNA damage induced p53 downregulates Cdc20 by direct binding to its promoter causing chromatin remodeling. Nucleic Acids Res 37:2688–2698
Dai L, Song ZX, Wei DP et al (2021) CDC20 and PTTG1 are important biomarkers and potential therapeutic targets for metastatic prostate Cancer. Adv Ther 38:2973–2989
Ding ZY, Wu HR, Zhang JM, Huang GR, Ji DD (2014) Expression characteristics of CDC20 in gastric cancer and its correlation with poor prognosis. Int J Clin Exp Pathol 7:722–727
Peng Q, Huang H, Zhu C et al (2022) CDC20 may serve as a potential biomarker-based risk score system in Predicting the prognosis of patients with Hepatocellular Carcinoma. Oxid Med Cell Longev 2022:8421813
Gao Y, Wen P, Chen B et al (2020) Downregulation of CDC20 increases radiosensitivity through Mcl-1/p-Chk1-Mediated DNA damage and apoptosis in Tumor cells. Int J Mol Sci 21
Zhao S, Zhang Y, Lu X et al (2021) CDC20 regulates the cell proliferation and radiosensitivity of P53 mutant HCC cells through the Bcl-2/Bax pathway. Int J Biol Sci 17:3608–3621
Wang Q, Wu L, Cao R et al (2022) Fbxo45 promotes the malignant development of esophageal squamous cell carcinoma by targeting GGNBP2 for ubiquitination and degradation. Oncogene 41:4795–4807
Wu L, Yu K, Chen K et al (2022) Fbxo45 facilitates pancreatic carcinoma progression by targeting USP49 for ubiquitination and degradation. Cell Death Dis 13:231
Wang J, Zhou K, Zhu H et al (2023) Current status and progress of the development of prostate cancer vaccines. J Cancer 14:835–842
Murgic J, Frobe A, Kiang Chua ML (2022) Recent advances in Radiotherapy Modalities for prostate Cancer. Acta Clin Croat 61:57–64
Shi J, Chen Y, Gu X, Wang X, Liu J, Chen X (2022) The Prognostic Assessment of CDC20 in patients with renal Clear Cell Carcinoma and its relationship with body immunity. Contrast Media Mol Imaging 2022:7727539
Cheng L, Huang YZ, Chen WX et al (2020) Cell division cycle proteinising prognostic biomarker of breast cancer. Biosci Rep 40
Qiu E, Gao Y, Zhang B, Xia T, Zhang Z, Shang G (2020) Upregulation of cell division cycle 20 in cisplatin resistance-induced epithelial-mesenchymal transition in osteosarcoma cells. Am J Transl Res 12:1309–1318
Wang L, Zhang J, Wan L, Zhou X, Wang Z, Wei W (2015) Targeting Cdc20 as a novel cancer therapeutic strategy. Pharmacol Ther 151:141–151
Volonte D, Sedorovitz M, Galbiati F (2022) Impaired Cdc20 signaling promotes senescence in normal cells and apoptosis in non-small cell lung cancer cells. J Biol Chem 298:102405
Cheng S, Castillo V, Sliva D (2019) CDC20 associated with cancer metastasis and novel mushroom–derived CDC20 inhibitors with antimetastatic activity. Int J Oncol 54:2250–2256
Ding Y, Zhang C, He L et al (2021) Apcin inhibits the growth and invasion of glioblastoma cells and improves glioma sensitivity to temozolomide. Bioengineered 12:10791–10798
Gao Y, Zhang B, Wang Y, Shang G (2018) Cdc20 inhibitor apcin inhibits the growth and invasion of osteosarcoma cells. Oncol Rep 40:841–848
Das T, Roy KS, Chakrabarti T, Mukhopadhyay S, Roychoudhury S (2014) Withaferin a modulates the spindle assembly checkpoint by degradation of Mad2-Cdc20 complex in colorectal cancer cell lines. Biochem Pharmacol 91:31–39
Gao Y, Guo C, Fu S, Cheng Y, Song C (2021) Downregulation of CDC20 suppressed cell proliferation, induced apoptosis, triggered cell cycle arrest in osteosarcoma cells, and enhanced chemosensitivity to cisplatin. Neoplasma 68:382–390
Simpson P (1983) Maternal-zygotic gene interactions during formation of the Dorsoventral Pattern in Drosophila embryos. Genetics 105:615–632
el Ghouzzi V, Le Merrer M, Perrin-Schmitt F et al (1997) Mutations of the TWIST gene in the Saethre-Chotzen syndrome. Nat Genet 15:42–46
Zhao Z, Rahman MA, Chen ZG, Shin DM (2017) Multiple biological functions of Twist1 in various cancers. Oncotarget 8:20380–20393
Wang X, Ling MT, Guan XY et al (2004) Identification of a novel function of TWIST, a bHLH protein, in the development of acquired taxol resistance in human cancer cells. Oncogene 23:474–482
Zhuo X, Chang A, Huang C et al (2015) Nanoparticle-mediated down-regulation of TWIST increases radiosensitivity of nasopharyngeal carcinoma cells via ERK pathway. Am J Cancer Res 5:1571–1579
Chen Y, Li L, Zeng J et al (2012) Twist confers chemoresistance to anthracyclines in bladder cancer through upregulating P-glycoprotein. Chemotherapy 58:264–272
Xiong H, Nie X, Zou Y et al (2017) Twist1 enhances Hypoxia Induced Radioresistance in Cervical Cancer cells by promoting Nuclear EGFR localization. J Cancer 8:345–353
Funding
This work was supported by CNNC science fund for talented young scholars (51010), and Suzhou Science and Technology Development Project (SYS2020139).
Author information
Authors and Affiliations
Contributions
CY, YG and YZ wrote the manuscript and performed experiments. MX, LJ, YW and XX performed the statistical analyses and edited the manuscript. BX and ZW conceived the experiemnts. LW conceived and designed the experiments, supervised the study, and revised the manuscript.
Corresponding authors
Ethics declarations
Ethical approval
All animal studies were approved by the Animal Experimentation Ethical Committee of Soochow University.
Competing interests
The authors have declared that no competing interest exists.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Yang, C., Ge, Y., Zang, Y. et al. CDC20 promotes radioresistance of prostate cancer by activating Twist1 expression. Apoptosis 28, 1584–1595 (2023). https://doi.org/10.1007/s10495-023-01877-7
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10495-023-01877-7