Abstract
Hepatocellular carcinoma (HCC) patients mostly suffer from poor survival outcomes. It is necessary to identify effective therapeutic targets to improve prognosis for HCC patients. Here, we report a new factor, CDCA2, in promoting HCC development. CDCA2 amplification is an independent risk factor for the recurrence and survival of HCC patients, which is positively correlated with elevated level of alpha-fetoprotein (AFP), high histological grade, large tumor size, advanced TNM stage, and poor prognosis for HCC patients. In HCC cells, CDCA2 promotes cell growth and inhibits apoptosis. Mechanistically, CDCA2’s transcription is activated through the binding of E2F2/E2F8 with its promoter. CDCA2 depletion contributes to the suppression of cell proliferation and induction of apoptosis due to reactive oxygen species (ROS)-mediated stress, which can be reversed by antioxidants N-acetyl cysteine (NAC) and glutathione (GSH). Interestingly, we found that CDCA2 triggers the BRCA1–NRF2 cascade, which elevates antioxidant response and attenuates ROS levels. In response to oxidative stress, CDCA2 promotes BRCA1’s chromatin relocalization to NRF2, activating NRF2-driven downstream signaling (HO-1, TXNRD1, and NQO1), which then protects HCC cells against oxidative damage. In conclusion, our results reveal that CDCA2 is a prognostic biomarker for HCC patients, and present the E2F2/E2F8–CDCA2–BRCA1–NRF2–ROS signaling axis that have implications for HCC therapeutics.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
All data are available from authors upon reasonable request.
References
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.
Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301–14.
Chen C, Chen S, Luo M, Yan H, Pang L, Zhu C, et al. The role of the CDCA gene family in ovarian cancer. Ann Transl Med. 2020;8:190–203.
Shen Z, Yu X, Zheng Y, Lai X, Li J, Hong Y, et al. CDCA5 regulates proliferation in hepatocellular carcinoma and has potential as a negative prognostic marker. Onco Targets Ther. 2018;11:891–901.
Thang PM, Takano A, Yoshitake Y, Shinohara M, Murakami Y, Daigo Y. Cell division cycle associated 1 as a novel prognostic biomarker and therapeutic target for oral cancer. Int J Oncol. 2016;49:1385–93.
Uchida F, Uzawa K, Kasamatsu A, Takatori H, Sakamoto Y, Ogawara K, et al. Overexpression of cell cycle regulator CDCA3 promotes oral cancer progression by enhancing cell proliferation with prevention of G1 phase arrest. BMC Cancer. 2012;12:321–30.
Wu B, Huang Y, Luo Y, Ma A, Wu Z, Gan Y, et al. The diagnostic and prognostic value of cell division cycle associated gene family in hepatocellular varcinoma. J Cancer. 2020;11:5727–37.
Xu Y, Wu X, Li F, Huang D, Zhu W. CDCA4, a downstream gene of the Nrf2 signaling pathway, regulates cell proliferation and apoptosis in the MCF7/ADM human breast cancer cell line. Mol Med Rep. 2018;17:1507–12.
Vagnarelli P. Repo-man at the intersection of chromatin remodelling, DNA repair, nuclear envelope organization, and cancer progression. Adv Exp Med Biol. 2014;773:401–14.
Shi R, Zhang C, Wu Y, Wang X, Sun Q, Sun J, et al. CDCA2 promotes lung adenocarcinoma cell proliferation and predicts poor survival in lung adenocarcinoma patients. Oncotarget. 2017;8:19768–79.
Zhang Y, Cheng Y, Zhang Z, Bai Z, Jin H, Guo X, et al. CDCA2 inhibits apoptosis and promotes cell proliferation in prostate cancer and is directly regulated by HIF-1alpha pathway. Front Oncol. 2020;10:725–37.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
Kim H, Kim YN, Kim H, Kim CW. Oxidative stress attenuates Fas-mediated apoptosis in Jurkat T cell line through Bfl-1 induction. Oncogene. 2005;24:1252–61.
Szatrowski TP, Nathan CF. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 1991;51:794–8.
Vafa O, Wade M, Kern S, Beeche M, Pandita TK, Hampton GM, et al. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol Cell. 2002;9:1031–44.
Sena LA, Chandel NS. Physiological roles of mitochondrial reactive oxygen species. Mol Cell. 2012;48:158–67.
Metallo CM, Vander, Heiden MG. Understanding metabolic regulation and its influence on cell physiology. Mol Cell. 2013;49:388–98.
Xu IM, Lai RK, Lin SH, Tse AP, Chiu DK, Koh HY, et al. Transketolase counteracts oxidative stress to drive cancer development. Proc Natl Acad Sci USA. 2016;113:E725–34.
Gorrini C, Baniasadi PS, Harris IS, Silvester J, Inoue S, Snow B, et al. BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival. J Exp Med. 2013;210:1529–44.
Xanthoulis A, Tiniakos DG. E2F transcription factors and digestive system malignancies: how much do we know? World J Gastroenterol. 2013;19:3189–98.
Huang JZ, Chen M, Zeng M, Xu SH, Zou FY, Chen D, et al. Down-regulation of TRPS1 stimulates epithelial-mesenchymal transition and metastasis through repression of FOXA1. J Pathol. 2016;239:186–96.
Huang G, Jiang H, He Y, Lin Y, Xia W, Luo Y, et al. LncMAPK6 drives MAPK6 expression and liver TIC self-renewal. J Exp Clin Cancer Res. 2018;37:105–16.
Chen X, Zhong Z, Xu Z, Chen L, Wang Y. 2’,7’-Dichlorodihydrofluorescein as a fluorescent probe for reactive oxygen species measurement: forty years of application and controversy. Free Radic Res. 2010;44:587–604.
Hill SJ, Rolland T, Adelmant G, Xia X, Owen MS, Dricot A, et al. Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage. Genes Dev. 2014;28:1957–75.
Bae I, Fan S, Meng Q, Rih JK, Kim HJ, Kang HJ, et al. BRCA1 induces antioxidant gene expression and resistance to oxidative stress. Cancer Res. 2004;64:7893–909.
Saha T, Rih JK, Rosen EM. BRCA1 down-regulates cellular levels of reactive oxygen species. FEBS Lett. 2009;583:1535–43.
Teng Y, Yadav T, Duan M, Tan J, Xiang Y, Gao B, et al. ROS-induced R loops trigger a transcription-coupled but BRCA1/2-independent homologous recombination pathway through CSB. Nat Commun. 2018;9:4115–27.
Cao L, Xu X, Cao LL, Wang RH, Coumoul X, Kim SS, et al. Absence of full-length Brca1 sensitizes mice to oxidative stress and carcinogen-induced tumorigenesis in the esophagus and forestomach. Carcinogenesis. 2007;28:1401–7.
Chen W, Sun Z, Wang XJ, Jiang T, Huang Z, Fang D, et al. Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response. Mol Cell. 2009;34:663–73.
Gorbunova V, Rezazadeh S, Seluanov A. Dangerous entrapment for NRF2. Cell 2016;165:1312–3.
Rezazadeh S, Yang D, Tombline G, Simon M, Regan SP, Seluanov A, et al. SIRT6 promotes transcription of a subset of NRF2 targets by mono-ADP-ribosylating BAF170. Nucleic Acids Res. 2019;47:7914–28.
Sugawara S, Yamada Y, Arai T, Okato A, Idichi T, Kato M, et al. Dual strands of the miR-223 duplex (miR-223-5p and miR-223-3p) inhibit cancer cell aggressiveness: targeted genes are involved in bladder cancer pathogenesis. J Hum Genet. 2018;63:657–68.
Baiz D, Dapas B, Farra R, Scaggiante B, Pozzato G, Zanconati F, et al. Bortezomib effect on E2F and cyclin family members in human hepatocellular carcinoma cell lines. World J Gastroenterol. 2014;20:795–803.
Zhan L, Huang C, Meng XM, Song Y, Wu XQ, Miu CG, et al. Promising roles of mammalian E2Fs in hepatocellular carcinoma. Cell Signal. 2014;26:1075–81.
Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12:931–47.
Panieri E, Santoro MM. ROS homeostasis and metabolism: a dangerous liason in cancer cells. Cell Death Dis. 2016;7:e2253–65.
Wang H, Liu X, Long M, Huang Y, Zhang L, Zhang R, et al. NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis. Sci Transl Med. 2016;8:334–51.
Jeong Y, Hoang NT, Lovejoy A, Stehr H, Newman AM, Gentles AJ, et al. Role of KEAP1/NRF2 and TP53 mutations in lung squamous cell carcinoma development and radiation resistance. Cancer Discov. 2017;7:86–101.
Wiel C, Le Gal K, Ibrahim MX, Jahangir CA, Kashif M, Yao H, et al. BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell. 2019;178:330–45.
Le Gal K, Ibrahim MX, Wiel C, Sayin VI, Akula MK, Karlsson C, et al. Antioxidants can increase melanoma metastasis in mice. Sci Transl Med. 2015;7:308
Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016;63:173–84.
DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 2011;475:106–9.
Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci USA. 2008;105:13568–73.
Chen D, Wang Y, Lu R, Jiang X, Chen X, Meng N. et al. E3 ligase ZFP91 inhibits hepatocellular carcinoma metabolism reprogramming by regulating PKM splicing. Theranostics. 2020;10:8558–72.
Huang JZ, Chen M, Chen, Gao XC, Zhu S, Huang H, et al. A peptide encoded by a putative lncRNA HOXB-AS3 suppresses colon cancer growth. Mol Cell. 2017;68:171–84.
El-Daher MT, Cagnard N, Gil M, Da Cruz MC, Leveau C, Sepulveda F, et al. Tetratricopeptide repeat domain 7A is a nuclear factor that modulates transcription and chromatin structure. Cell Discov. 2018;4:61–81.
Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47:556–60.
Zou Y, Lu Q, Yao Q, Dong D, Chen B. Identification of novel prognostic biomarkers in renal cell carcinoma. Aging (Albany NY). 2020;12:25304–18.
Subramanian A, Kuehn H, Gould J, Tamayo P, Mesirov JP. GSEA-P: a desktop application for Gene Set Enrichment Analysis. Bioinformatics. 2007;23:3251–3.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 81672393), Science and technology project of Guangzhou (No. 201707010379), Natural Science Youth Project of the Third Affiliated Hospital of Guangzhou Medical University (No. 2019Q07, 2019B06), the National Natural Science Foundation of China (82002104, to KC), Guangdong Basic and Applied Basic Research Foundation (2019A1515110659, to KC).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Wang, S., Cao, K., Liao, Y. et al. CDCA2 protects against oxidative stress by promoting BRCA1–NRF2 signaling in hepatocellular carcinoma. Oncogene 40, 4368–4383 (2021). https://doi.org/10.1038/s41388-021-01855-w
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-021-01855-w
This article is cited by
-
Targeting DDX11 promotes PARP inhibitor sensitivity in hepatocellular carcinoma by attenuating BRCA2-RAD51 mediated homologous recombination
Oncogene (2024)
-
Identification of G protein subunit alpha i2 as a promising therapeutic target of hepatocellular carcinoma
Cell Death & Disease (2023)
-
Inhibition of CXorf56 promotes PARP inhibitor-induced cytotoxicity in triple-negative breast cancer
npj Breast Cancer (2023)
-
Hops extract and xanthohumol ameliorate bone loss induced by iron overload via activating Akt/GSK3β/Nrf2 pathway
Journal of Bone and Mineral Metabolism (2022)