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

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.

ATF2; Ferroptosis; Gastric cancer; HSPH1; Sorafenib.