Increased ATF2 expression predicts poor prognosis and inhibits sorafenib-induced ferroptosis in gastric cancer

• Published in: Redox biology Vol. 59; p. 102564
• Main Authors: Xu, Xin, Li, Yaxian, Wu, Youliang, Wang, Mingliang, Lu, Yida, Fang, Ziqing, Wang, Huizhen, Li, Yongxiang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2023; Elsevier
• Subjects: Activating Transcription Factor 2 - genetics; Activating Transcription Factor 2 - pharmacology; Animals; ATF2; Cell Line, Tumor; Disease Models, Animal; Ferroptosis; Gastric cancer; HSPH1; Humans; Phenotype; Research Paper; Sorafenib; Sorafenib - pharmacology; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; ATF2; Ferroptosis; HSPH1; Gastric cancer; Sorafenib
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2022.102564

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.