The m(6)A reader YTHDC2 inhibits lung adenocarcinoma tumorigenesis by suppressing SLC7A11-dependent antioxidant function

The biological functions of N6-methyladenosine (m(6)A) RNA methylation are mainly dependent on the reader; however, its role in lung tumorigenesis remains unclear. Here, we have demonstrated that the m(6)A 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 m(6)A-recognizing YTH domain, suppressed cystine uptake and blocked the downstream antioxidant program Administration of cystine downstream antioxidants to pulmonary YTHDC2overexpressing mice rescued lung tumorigenesis. Furthermore, solute carrier 7A11 (SLC7A11), the catalytic subunit of system XE, was identified to be the direct target of YTHDC2. YTHDC2 destabilized SLC7A11 mRNA in an m(6)A-dependent manner because YTHDC2 preferentially bound to m 6 A-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 XE 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.

Automated summary

The m(6)A reader YTHDC2 is frequently suppressed in lung adenocarcinoma, leading to poor clinical outcomes, and it exerts antitumor activity by suppressing cystine uptake via system XE. Downregulation of YTHDC2 destabilizes SLC7A11 mRNA in an m(6)A-dependent manner, implicating the modulation of cystine uptake in promoting lung adenocarcinoma tumorigenesis.