Increased ATF2 expression predicts poor prognosis and inhibits sorafenib-induced ferroptosis in gastric cancer.
Increased ATF2 expression predicts poor prognosis and inhibits sorafenib-induced ferroptosis in gastric cancer.
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DOI：
10.1016/j.redox.2022.102564
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发表时间：
2023-02
期刊：
影响因子：
11.4
通讯作者：
Li, Yongxiang
中科院分区：
文献类型：
--
作者：
Xu, Xin;Li, Yaxian;Wu, Youliang;Wang, Mingliang;Lu, Yida;Fang, Ziqing;Wang, Huizhen;Li, Yongxiang
索拉非尼是一种酪氨酸激酶抑制剂，在包括胃癌(GC)在内的多种癌症中作为铁下垂诱导剂具有重要的抗肿瘤作用。然而，索拉非尼作为铁下垂诱导剂的地位最近受到了质疑。关于铁下垂和ATF2之间的关系的信息非常有限，而且ATF2在索拉非尼诱导的铁下垂中的作用还没有被研究过。在这项研究中，我们研究了ATF2在索拉非尼诱导的GC铁下垂中的作用和潜在的分子机制。我们发现ATF2在胃癌组织中显著上调，并预示着不良的临床预后。沉默ATF2可显著抑制GC细胞的恶性表型。此外，我们观察到，在索拉非尼诱导的GC细胞铁下垂过程中，ATF2被激活。ATF2基因敲除促进了索拉非尼诱导的铁下垂，而ATF2过表达则在GC细胞中显示相反的结果。利用CHIP-Seq和RNA-Seq，我们确定了HSPH1为ATF2的靶标，并通过CHIP-qPCR分析进一步验证了其有效性。HSPH1可与半胱氨酸/谷氨酸转运体SLC7A11相互作用，提高其蛋白质稳定性。重要的是，HSPH1的敲除部分逆转了ATF2过表达对索拉非尼诱导的GC细胞铁下垂的影响。另外，异种移植瘤模型的实验结果表明，ATF2基因敲除可有效增强体内索拉非尼的敏感性。总而言之，我们的研究揭示了索拉非尼诱导GC中铁下垂的新机制。
Sorafenib, a tyrosine kinase inhibitor, has an important antitumor effect as a ferroptosis inducer in multiple cancers, including gastric cancer (GC). However, the status of sorafenib as a ferroptosis inducer has recently been questioned. There is very limited information about the relationship between ferroptosis and ATF2, and the role of ATF2 in sorafenib-induced ferroptosis has not been studied. In this study, we investigated the role and underlying molecular mechanisms of ATF2 in sorafenib-induced ferroptosis in GC. We found that ATF2 was significantly upregulated in GC tissues and predicted a poor clinical prognosis. Silencing ATF2 significantly inhibited the malignant phenotype of GC cells. In addition, we observed that ATF2 was activated during sorafenib-induced ferroptosis in GC cells. ATF2 knockdown promoted sorafenib-induced ferroptosis, while ATF2 overexpression showed the opposite results in GC cells. Using ChIP-Seq and RNA-Seq, we identified HSPH1 as a target of ATF2 and further validated it by ChIP‒qPCR analysis. HSPH1 can interact with SLC7A11 (cystine/glutamate transporter) and increase its protein stability. Importantly, knockdown of HSPH1 partly reversed the effects caused by ATF2 overexpression on sorafenib-induced ferroptosis in GC cells. In addition, the results from the tumor xenograft model showed that ATF2 knockdown can effectively enhance sorafenib sensitivity in vivo. Collectively, our study reveals a novel mechanism by which sorafenib induces ferroptosis in GC.
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影响因子：
11.4
作者：
Sun J;Zhou C;Zhao Y;Zhang X;Chen W;Zhou Q;Hu B;Gao D;Raatz L;Wang Z;Nelson PJ;Jiang Y;Ren N;Bruns CJ;Zhou H
通讯作者：
Zhou H
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
2.9
作者：
Inoue, Satoshi;Mizushima, Taichi;Miyamoto, Hiroshi
通讯作者：
Miyamoto, Hiroshi
影响因子：
9
作者：
Cheng, Qi;Chen, Mo;Liu, Mengdan;Chen, Xin;Zhu, Lingjiang;Xu, Jieying;Xue, Jing;Wu, Huaxiang;Du, Yan
通讯作者：
Du, Yan
影响因子：
5.5
作者：
通讯作者：
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