IGF2BP3 is an essential N6-methyladenosine biotarget for suppressing ferroptosis in lung adenocarcinoma cells

作者：Xin Xu, Jiangtao Cui, Hong Wang, Lifang Ma, Xiao Zhang, Wanxin Guo, Xiangfei Xue, Yikun Wang, Shiyu Qiu, Xiaoting Tian, Yayou Miao, Mengyi Wu, Yongchun Yu, Yunhua Xu, Jiayi Wang, Yongxia Qiao · 发表于：Materials Today Bio · 年份：2022 · DOI：10.1016/j.mtbio.2022.100503 · 被引用次数：88 · 研究领域：RNA modifications and cancer、Cancer-related molecular mechanisms research、Ferroptosis and cancer prognosis

A lack of promising targets leads to poor prognosis in patients with lung adenocarcinoma (LUAD). Therefore, it is urgent to identify novel therapeutic targets. The importance of the N 6 -methyladenosine (m 6 A) RNA modification has been demonstrated in various types of tumors; however, knowledge of m 6 A-related proteins in LUAD is still limited. Here, we found that insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), an m 6 A reader protein, is highly expressed in LUAD and associated with poor prognosis. IGF2BP3 desensitizes ferroptosis (a new form of regulated cell death) in a manner dependent on its m 6 A reading domain and binding capacity to m 6 A-methylated mRNAs encoding anti-ferroptotic factors, including but not limited to glutathione peroxidase 4 (GPX4), solute carrier family 3 member 2 (SLC3A2), acyl-CoA synthetase long chain family member 3 (ACSL3), and ferritin heavy chain 1 (FTH1). After IGF2BP3 overexpression, expression levels and mRNA stabilities of these anti-ferroptotic factors were successfully sustained. Notably, significant correlations between SLC3A2, ACSL3, and IGF2BP3 were revealed in clinical LUAD specimens, further establishing the essential role of IGF2BP3 in desensitizing ferroptosis. Inducing ferroptosis has been gradually accepted as an alternative strategy to treat tumors. Thus, IGF2BP3 could be a potential target for the future development of new biomaterial-associated therapeutic anti-tumor drugs.