Loss of cell division cycle‑associated 5 promotes cell apoptosis by activating DNA damage response in clear cell renal cell carcinoma

Huang,Xing; Huang,Yan; Lv,Zheng; Wang,Tao; Feng,Huayi; Wang,Hanfeng; Du,Songliang; Wu,Shengpan; Shen,Donglai; Wang,Chenfeng; Li,Hongzhao; Wang,Baojun; Ma,Xin; Zhang,Xu

doi:10.3892/ijo.2022.5377

Loss of cell division cycle‑associated 5 promotes cell apoptosis by activating DNA damage response in clear cell renal cell carcinoma

Authors:
- Xing Huang
- Yan Huang
- Zheng Lv
- Tao Wang
- Huayi Feng
- Hanfeng Wang
- Songliang Du
- Shengpan Wu
- Donglai Shen
- Chenfeng Wang
- Hongzhao Li
- Baojun Wang
- Xin Ma
- Xu Zhang
View Affiliations

Affiliations: Department of Urology, The Third Medical Center, Chinese PLA General Hospital/Medical School of Chinese PLA/State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing 100853, P.R. China, Department of Urology, The Third Affiliated Central Hospital of Nankai University, Tianjin 300071, P.R. China
Published online on: May 31, 2022 https://doi.org/10.3892/ijo.2022.5377
Article Number: 87
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cell division cycle‑associated 5 (CDCA5) protein, which is involved in cohesion, contributes to cell cycle regulation and chromosome segregation by maintaining genomic stability. Accumulating evidence indicates that CDCA5 expression is upregulated in a number of types of cancer associated with a poor prognosis. However, the biological function of CDCA5 in clear cell renal cell carcinoma (ccRCC) remains largely unknown. In the present study, The Cancer Genome Atlas data mining revealed that CDCA5 was more highly expressed in ccRCC than in adjacent normal tissues. Importantly, such a high expression was associated with a higher risk of distant metastasis and poorer clinical outcomes. Moreover, the clinical and prognostic value of CDCA5 expression was further investigated using immunohistochemistry on tissue microarrays containing paired tumor tissues and adjacent normal tissues from 137 patients with ccRCC. Functional analyses revealed that CDCA5 knockdown significantly inhibited the proliferation and migration of ccRCC cells, and suppressed the growth of xenografts in nude mice. Mechanistically, CDCA5 knockdown induced severe DNA damage with the persistent accumulation of γ‑H2A histone family member X foci, resulting in G2/M cell cycle arrest and finally, in chromosomal instability and apoptosis. CDCA5 knockdown significantly decreased the phosphorylation levels of Stat3 and NF‑κB, suggesting that CDCA5 plays a role in regulating the inflammatory response. Collectively, the findings of the present study indicate that ccRCC cells require CDCA5 for malignant progression, and that CDCA5 inhibition may enhance the outcomes of patients with high‑risk ccRCC.

View Figures

View References

1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Ricketts CJ, De Cubas AA, Fan H, Smith CC, Lang M, Reznik E, Bowlby R, Gibb EA, Akbani R, Beroukhim R, et al: The cancer genome atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 23:313–326.e5. 2018. View Article : Google Scholar : PubMed/NCBI
3	Cancer Genome Atlas and Research Network: Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 499:43–49. 2013. View Article : Google Scholar
4	Vasan N, Baselga J and Hyman DM: A view on drug resistance in cancer. Nature. 575:299–309. 2019. View Article : Google Scholar : PubMed/NCBI
5	Peters JM: The anaphase promoting complex/cyclosome: A machine designed to destroy. Nat Rev Mol Cell Biol. 7:644–656. 2006. View Article : Google Scholar : PubMed/NCBI
6	Rankin S, Ayad NG and Kirschner MW: Sororin, a substrate of the anaphase-promoting complex, is required for sister chromatid cohesion in vertebrates. Mol Cell. 18:185–200. 2005. View Article : Google Scholar : PubMed/NCBI
7	Haarhuis JHI, Elbatsh AMO and Rowland BD: Cohesin and its regulation: On the logic of X-shaped chromosomes. Dev Cell. 31:7–18. 2014. View Article : Google Scholar : PubMed/NCBI
8	Ladurner R, Kreidl E, Ivanov MP, Ekker H, Idarraga-Amado MH, Busslinger GA, Wutz G, Cisneros DA and Peters JM: Sororin actively maintains sister chromatid cohesion. EMBO J. 35:635–653. 2016. View Article : Google Scholar : PubMed/NCBI
9	Sjögren C and Nasmyth K: Sister chromatid cohesion is required for postreplicative double-strand break repair in Saccharomyces cerevisiae. Curr Biol. 11:991–995. 2001. View Article : Google Scholar : PubMed/NCBI
10	Watrin E and Peters JM: The cohesin complex is required for the DNA damage-induced G2/M checkpoint in mammalian cells. EMBO J. 28:2625–2635. 2009. View Article : Google Scholar : PubMed/NCBI
11	Gruber S, Haering CH and Nasmyth K: Chromosomal cohesin forms a ring. Cell. 112:765–777. 2003. View Article : Google Scholar : PubMed/NCBI
12	Zhang N and Pati D: Sororin is a master regulator of sister chromatid cohesion and separation. Cell Cycle. 11:2073–2083. 2012. View Article : Google Scholar : PubMed/NCBI
13	Tian Y, Wu J, Chagas C, Du Y, Lyu H, He Y, Qi S, Peng Y and Hu J: CDCA5 overexpression is an Indicator of poor prognosis in patients with hepatocellular carcinoma (HCC). BMC Cancer. 18:11872018. View Article : Google Scholar : PubMed/NCBI
14	Shen A, Liu L, Chen H, Qi F, Huang Y, Lin J, Sferra TJ, Sankararaman S, Wei L, Chu J, et al: Cell division cycle associated 5 promotes colorectal cancer progression by activating the ERK signaling pathway. Oncogenesis. 8:192019. View Article : Google Scholar : PubMed/NCBI
15	Chang IW, Lin VCH, He HL, Hsu CT, Li CC, Wu WJ, Huang CN, Wu TF and Li CF: CDCA5 overexpression is an indicator of poor prognosis in patients with urothelial carcinomas of the upper urinary tract and urinary bladder. Am J Transl Res. 7:710–722. 2015.PubMed/NCBI
16	Fu G, Xu Z, Chen X, Pan H, Wang Y and Jin B: CDCA5 functions as a tumor promoter in bladder cancer by dysregulating mitochondria-mediated apoptosis, cell cycle regulation and PI3k/AKT/mTOR pathway activation. J Cancer. 11:2408–2420. 2020. View Article : Google Scholar : PubMed/NCBI
17	Paner GP, Stadler WM, Hansel DE, Montironi R, Lin DW and Amin MB: Updates in the eighth edition of the tumor-node-metastasis staging classification for urologic cancers. Eur Urol. 73:560–569. 2018. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
19	Saremi N and Lam AK: Application of tissue microarray in esophageal adenocarcinoma. Methods Mol Biol. 1756:105–118. 2018. View Article : Google Scholar : PubMed/NCBI
20	Faustino-Rocha A, Oliveira PA, Pinho-Oliveira J, Teixeira-Guedes C, Soares-Maia R, da Costa RG, Colaço B, Pires MJ, Colaço J, Ferreira R and Ginja M: Estimation of rat mammary tumor volume using caliper and ultrasonography measurements. Lab Anim (NY). 42:217–224. 2013. View Article : Google Scholar
21	Ma N, Kawanishi M, Hiraku Y, Murata M, Huang GW, Huang Y, Luo DZ, Mo WG, Fukui Y and Kawanishi S: Reactive nitrogen species-dependent DNA damage in EBV-associated nasopharyngeal carcinoma: The relation to STAT3 activation and EGFR expression. Int J Cancer. 122:2517–2525. 2008. View Article : Google Scholar : PubMed/NCBI
22	Hanahan D: Hallmarks of cancer: New dimensions. Cancer Discov. 12:31–46. 2022. View Article : Google Scholar : PubMed/NCBI
23	Ui A, Chiba N and Yasui A: Relationship among DNA double-strand break (DSB), DSB repair, and transcription prevents genome instability and cancer. Cancer Sci. 111:1443–1451. 2020. View Article : Google Scholar : PubMed/NCBI
24	Waldman T: Emerging themes in cohesin cancer biology. Nat Rev Cancer. 20:504–515. 2020. View Article : Google Scholar : PubMed/NCBI
25	Xu J, Zhu C, Yu Y, Wu W, Cao J, Li Z, Dai J, Wang C, Tang Y, Zhu Q, et al: Systematic cancer-testis gene expression analysis identified CDCA5 as a potential therapeutic target in esophageal squamous cell carcinoma. EBioMedicine. 46:54–65. 2019. View Article : Google Scholar : PubMed/NCBI
26	Chen H, Chen J, Zhao L, Song W, Xuan Z, Chen J, Li Z, Song G, Hong L, Song P and Zheng S: CDCA5, Transcribed by E2F1, promotes oncogenesis by enhancing cell proliferation and inhibiting apoptosis via the AKT pathway in hepatocellular carcinoma. J Cancer. 10:1846–1854. 2019. View Article : Google Scholar : PubMed/NCBI
27	Nguyen MH, Koinuma J, Ueda K, Ito T, Tsuchiya E, Nakamura Y and Daigo Y: Phosphorylation and activation of cell division cycle associated 5 by mitogen-activated protein kinase play a crucial role in human lung carcinogenesis. Cancer Res. 70:5337–5347. 2010. View Article : Google Scholar : PubMed/NCBI
28	Nowak SJ and Corces VG: Phosphorylation of histone H3: A balancing act between chromosome condensation and transcriptional activation. Trends Genet. 20:214–220. 2004. View Article : Google Scholar : PubMed/NCBI
29	Lord CJ and Ashworth A: PARP inhibitors: Synthetic lethality in the clinic. Science. 355:1152–1158. 2017. View Article : Google Scholar : PubMed/NCBI
30	Mittal P and Roberts CWM: The SWI/SNF complex in cancer-biology, biomarkers and therapy. Nat Rev Clin Oncol. 17:435–448. 2020. View Article : Google Scholar : PubMed/NCBI
31	Nishiyama T, Ladurner R, Schmitz J, Kreidl E, Schleiffer A, Bhaskara V, Bando M, Shirahige K, Hyman AA, Mechtler K and Peters JM: Sororin mediates sister chromatid cohesion by antagonizing Wapl. Cell. 143:737–749. 2010. View Article : Google Scholar : PubMed/NCBI
32	Losada A: Cohesin in cancer: Chromosome segregation and beyond. Nat Rev Cancer. 14:389–393. 2014. View Article : Google Scholar : PubMed/NCBI
33	Bednarski JJ and Sleckman BP: At the intersection of DNA damage and immune responses. Nat Rev Immunol. 19:231–242. 2019. View Article : Google Scholar : PubMed/NCBI
34	Chen Q, Sun L and Chen ZJ: Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat Immunol. 17:1142–1149. 2016. View Article : Google Scholar : PubMed/NCBI
35	Cai X, Chiu YH and Chen ZJ: The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. Mol Cell. 54:289–296. 2014. View Article : Google Scholar : PubMed/NCBI
36	Ishikawa H, Ma Z and Barber GN: STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature. 461:788–792. 2009. View Article : Google Scholar : PubMed/NCBI
37	Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P and Rice CM: A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 472:481–485. 2011. View Article : Google Scholar : PubMed/NCBI
38	Wang J, Lv X, Guo X, Dong Y, Peng P, Huang F, Wang P, Zhang H, Zhou J, Wang Y, et al: Feedback activation of STAT3 limits the response to PI3K/AKT/mTOR inhibitors in PTEN-deficient cancer cells. Oncogenesis. 10:82021. View Article : Google Scholar : PubMed/NCBI
39	Reisländer T, Groelly FJ and Tarsounas M: DNA damage and cancer immunotherapy: A STING in the Tale. Mol Cell. 80:21–28. 2020. View Article : Google Scholar : PubMed/NCBI
40	Danial NN and Korsmeyer SJ: Cell death: Critical control points. Cell. 116:205–219. 2004. View Article : Google Scholar : PubMed/NCBI
41	Schreiber V, Dantzer F, Ame JC and de Murcia G: Poly(ADP-ribose): Novel functions for an old molecule. Nat Rev Mol Cell Biol. 7:517–528. 2006. View Article : Google Scholar : PubMed/NCBI
42	Malanga M and Althaus FR: The role of poly(ADP-ribose) in the DNA damage signaling network. Biochem Cell Biol. 83:354–364. 2005. View Article : Google Scholar : PubMed/NCBI
43	Schumacher TN and Schreiber RD: Neoantigens in cancer immunotherapy. Science. 348:69–74. 2015. View Article : Google Scholar : PubMed/NCBI