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CDCA2 protects against oxidative stress by promoting BRCA1–NRF2 signaling in hepatocellular carcinoma

Oncogene volume 40, pages 4368–4383 (2021)Cite this article

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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.

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Fig. 1: CDCA2 is overexpressed in HCC, which is positively associated with a poor prognosis of HCC patients.
Fig. 2: CDCA2 promotes HCC cell proliferation and inhibits HCC cell apoptosis.
Fig. 3: CDCA2 is a critical effector for E2F2/E2F8 transcription factors in regulation of HCC cell proliferation and apoptosis.
Fig. 4: CDCA2 transcription is co-activated by E2F2 and E2F8 binding to CDCA2 promoter.
Fig. 5: CDCA2 upregulated by E2F2/E2F8 promotes HCC cell malignant phenotypes via reducing ROS accumulation.
Fig. 6: ROS levels suppressed by the E2F2/E2F8–CDCA2 signaling axis are associated with worse outcomes of HCC patients.
Fig. 7: CDCA2 promotes BRCA1–NRF2 complex against oxidative stress in HCC cells.
Fig. 8: The proposed model for CDCA2 in the ROS pathway.

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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).

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  1. These authors contributed equally: Shouping Wang, Kun Cao, Yuting Liao, Wei Zhang

Authors and Affiliations

  1. Department of Anesthesiology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Shouping Wang, Wei Zhang, Xiaocui Li, Mengting Huang & Yanjie Wang

  2. Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Aging Research, Guangdong Medical University, Dongguan, China

    Kun Cao

  3. Department of Radiotherapy, General Hospital of Southern Theater Command, Guangzhou, China

    Yuting Liao & Jihua Zheng

  4. Department of Surgery, The Second People’s Hospital of Shenzhen Futian District, Shenzhen, China

    Yonghao Zhong

  5. Department of Surgery, The Second People’s Hospital of Guangdong Province, Guangzhou, China

    Xiao Hu

  6. Biomedicine Research Center, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    De Chen & Yanjie Wang

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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

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