2. Academic Validation
  3. The m6A reader YTHDC2 inhibits lung adenocarcinoma tumorigenesis by suppressing SLC7A11-dependent antioxidant function

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

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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