CDCA2 protects against oxidative stress by promoting BRCA1-NRF2 signaling in hepatocellular carcinoma
CDCA2 protects against oxidative stress by promoting BRCA1-NRF2 signaling in hepatocellular carcinoma
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DOI：
10.1038/s41388-021-01855-w
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发表时间：
2021-06-08
期刊：
影响因子：
8
通讯作者：
Wang, Yanjie
中科院分区：
文献类型：
--
作者：
Wang, Shouping;Cao, Kun;Wang, Yanjie
肝细胞癌（HCC）患者大多存在较差的生存结果。寻找有效的治疗靶点，改善HCC患者预后是十分必要的。在这里，我们报道了一个新的因子CDCA2在促进HCC发展中的作用。CDCA2扩增是HCC患者复发和生存的独立危险因素，与HCC患者甲胎蛋白（AFP）水平升高、组织学分级高、肿瘤大小大、TNM分期晚期、预后差呈正相关。在HCC细胞中，CDCA2促进细胞生长并抑制细胞凋亡。机制上，CDCA2的转录是通过E2F2/E2F8与其启动子的结合而激活的。CDCA2缺失有助于抑制活性氧（ROS）介导的应激引起的细胞增殖和诱导凋亡，这可以通过抗氧化剂n -乙酰半胱氨酸（NAC）和谷胱甘肽（GSH）逆转。有趣的是，我们发现CDCA2触发BRCA1-NRF2级联，从而提高抗氧化反应并降低ROS水平。在氧化应激反应中，CDCA2促进BRCA1的染色质重新定位到NRF2，激活NRF2驱动的下游信号（HO-1， TXNRD1和NQO1），从而保护HCC细胞免受氧化损伤。总之，我们的研究结果表明，CDCA2是HCC患者的预后生物标志物，并且存在E2F2/E2F8-CDCA2-BRCA1-NRF2-ROS信号轴，对HCC治疗有影响。
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.