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

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

doi:10.1016/j.mtbio.2022.100503

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

Mater Today Bio. 2022 Nov 24:17:100503. doi: 10.1016/j.mtbio.2022.100503. eCollection 2022 Dec 15.

Authors

Xin Xu^{1

2}, Jiangtao Cui³, Hong Wang⁴, Lifang Ma¹, Xiao Zhang², Wanxin Guo², Xiangfei Xue¹, Yikun Wang¹, Shiyu Qiu², Xiaoting Tian², Yayou Miao², Mengyi Wu⁵, Yongchun Yu², Yunhua Xu⁶, Jiayi Wang^{1

2

7}, Yongxia Qiao⁴

Affiliations

¹ Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 200030, China.
² Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 200030, China.
³ Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 200030, China.
⁴ School of Public Health, Shanghai Jiao Tong University School of Medicine, 200025, China.
⁵ Shanghai University of Traditional Chinese Medicine, 201203, China.
⁶ Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China.
⁷ College of Medical Technology, Shanghai Jiao Tong University School of Medicine, 200025, China.

Abstract

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 N⁶-methyladenosine (m⁶A) RNA modification has been demonstrated in various types of tumors; however, knowledge of m⁶A-related proteins in LUAD is still limited. Here, we found that insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), an m⁶A 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 m⁶A reading domain and binding capacity to m⁶A-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.

Keywords: ACSL3, acyl-CoA synthetase long chain family member 3; ALKBH5, alkB homolog 5; ELISA, enzyme-linked immunosorbent assay; FTH1, ferritin heavy chain 1; FTO, fat mass-and obesity-associated gene; Ferroptosis; GPX4, glutathione peroxidase 4; HNRNPA2B1, heterogeneous nuclear ribonucleoprotein A2/B1; IB, immunoblotting; IGF2BP3, insulin-like growth factor 2 mRNA binding protein 3; IHC, immunohistochemistry; LUAD, lung adenocarcinoma; Lung adenocarcinoma; MDA, malondialdehyde; METTL14, methyltransferase-like 14; METTL3, methyltransferase-like 3; PKM, pyruvate kinase M1/2; RBM15, RNA binding motif protein 15; ROS, reactive oxygen species; SLC3A2, solute carrier family 3 member 2; TMA, tissue microarray assay; Therapeutic target; VIRMA, vir-like m6A methyltransferase associated; WTAP, Wilms' tumor 1-associating protein; YTHDF2, YTH domain family 2; ZC3H13, zinc finger CCCH-type containing 13; m6A RNA methylation; m6A reader; m6A, N6-methyladenosine; qRT-PCR, quantitative reverse transcription PCR.