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.
Lifang Ma  1 ,  Tianxiang Chen  2 ,  Xiao Zhang  3 ,  Yayou Miao  3 ,  Xiaoting Tian  3 ,  Keke Yu  4 ,  Xin Xu  3 ,  Yongjie Niu  5 ,  Susu Guo  6 ,  Congcong Zhang  5 ,  Shiyu Qiu  3 ,  Yongxia Qiao  7 ,  Wentao Fang  8 ,  Lutao Du  9 ,  Yongchun Yu  10 ,  Jiayi Wang  11
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: [email protected].
  • 10. Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China. Electronic address: [email protected].
  • 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: [email protected].
PMID: 33232910 DOI: 10.1016/j.redox.2020.101801
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 XC-, 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 XC- 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.
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