The m6A reader YTHDC2 inhibits lung adenocarcinoma tumorigenesis by suppressing SLC7A11-dependent antioxidant function

Lifang Ma; Tianxiang Chen; Xiao Zhang; Yayou Miao; Xiaoting Tian; Keke Yu; Xin Xu; Yongjie Niu; Susu Guo; Congcong Zhang; Shiyu Qiu; Yongxia Qiao; Wentao Fang; Lutao Du; Yongchun Yu; Jiayi Wang

doi:10.1016/j.redox.2020.101801

The m⁶A reader YTHDC2 inhibits lung adenocarcinoma tumorigenesis by suppressing SLC7A11-dependent antioxidant function

Redox Biol. 2021 Jan:38:101801. doi: 10.1016/j.redox.2020.101801. Epub 2020 Nov 18.

Authors

Lifang Ma¹, Tianxiang Chen², Xiao Zhang³, Yayou Miao³, Xiaoting Tian³, Keke Yu⁴, Xin Xu³, Yongjie Niu⁵, Susu Guo⁶, Congcong Zhang⁵, Shiyu Qiu³, Yongxia Qiao⁷, Wentao Fang⁸, Lutao Du⁹, Yongchun Yu¹⁰, Jiayi Wang¹¹

Affiliations

¹ Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
² Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
³ Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
⁴ Department of Bio-bank, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
⁵ Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
⁶ Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China.
⁷ School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
⁸ Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
⁹ Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, 250033, Shandong province, China. Electronic address: lutaodu@sdu.edu.cn.
¹⁰ Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China. Electronic address: yyc2166@sjtu.edu.cn.
¹¹ Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China; Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China. Electronic address: karajan2@163.com.

Abstract

The biological functions of N6-methyladenosine (m⁶A) RNA methylation are mainly dependent on the reader; however, its role in lung tumorigenesis remains unclear. Here, we have demonstrated that the m⁶A reader YT521-B homology domain containing 2 (YTHDC2) is frequently suppressed in lung adenocarcinoma (LUAD). Downregulation of YTHDC2 was associated with poor clinical outcome of LUAD. YTHDC2 decreased tumorigenesis in a spontaneous LUAD mouse model. Moreover, YTHDC2 exhibited antitumor activity in human LUAD cells. Mechanistically, YTHDC2, via its m⁶A-recognizing YTH domain, suppressed cystine uptake and blocked the downstream antioxidant program. Administration of cystine downstream antioxidants to pulmonary YTHDC2-overexpressing mice rescued lung tumorigenesis. Furthermore, solute carrier 7A11 (SLC7A11), the catalytic subunit of system X_C^-, was identified to be the direct target of YTHDC2. YTHDC2 destabilized SLC7A11 mRNA in an m⁶A-dependent manner because YTHDC2 preferentially bound to m⁶A-modified SLC7A11 mRNA and thereafter promoted its decay. Clinically, a large proportion of acinar LUAD subtype cases exhibited simultaneous YTHDC2 downregulation and SLC7A11 elevation. Patient-derived xenograft (PDX) mouse models generated from acinar LUAD showed sensitivity to system X_C^- inhibitors. Collectively, the promotion of cystine uptake via the suppression of YTHDC2 is critical for LUAD tumorigenesis, and blocking this process may benefit future treatment.

Keywords: Cystine uptake; Lipid peroxidation; METTL3; System X(C)(−); m(6)A RNA methylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma of Lung* / drug therapy
Adenocarcinoma of Lung* / genetics
Animals
Antioxidants
Carcinogenesis / genetics
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Mice
RNA Helicases

Substances

Antioxidants
RNA Helicases