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

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.

SUBMITTER: Ma L

PROVIDER: S-EPMC7691619 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundN6-methyladenosine (m6A) has emerged as a significant regulator of the progress of various cancers. However, its role in lung adenocarcinoma (LUAD) remains unclear. Here, we explored the biological function and underlying mechanism of methyltransferase-like 3 (METTL3), the main catalyst of m6A, in LUAD progression.MethodsThe expression of m6A, METTL3, YTHDF1 and SLC7A11 were detected by immunochemistry or/and online datasets in LUAD patients. The effects of METTL3 on LUAD cell proliferation, apoptosis and ferroptosis were assessed through in vitro loss-and gain-of-function experiments. The in vivo effect on tumorigenesis of METTL3 was evaluated using the LUAD cell xenograft mouse model. MeRIP-seq, RNA immunoprecipitation and RNA stability assay were conducted to explore the molecular mechanism of METTL3 in LUAD.ResultsThe results showed that the m6A level, as well as the methylase METTL3 were both significantly elevated in LUAD patients and lung cancer cells. Functionally, we found that METTL3 could promote proliferation and inhibit ferroptosis in different LUAD cell models, while METTL3 knockdown suppressed LUAD growth in cell-derived xenografts. Mechanistically, solute carrier 7A11 (SLC7A11), the subunit of system Xc-, was identified as the direct target of METTL3 by mRNA-seq and MeRIP-seq. METTL3-mediated m6A modification could stabilize SLC7A11 mRNA and promote its translation, thus promoting LUAD cell proliferation and inhibiting cell ferroptosis, a novel form of programmed cell death. Additionally, we demonstrated that YTHDF1, a m6A reader, was recruited by METTL3 to enhance SLC7A11 m6A modification. Moreover, the expression of YTHDF1 and SLC7A11 were positively correlated with METTL3 and m6A in LUAD tissues.ConclusionsThese findings reinforced the oncogenic role of METTL3 in LUAD progression and revealed its underlying correlation with cancer cell ferroptosis; these findings also indicate that METTL3 is a promising novel target in LUAD diagnosis and therapy.

Project description:BACKGROUND:m6 A modification affects the pathological progress of many diseases by affecting RNA stability and translocation. YTHDC2, a m6 A reader, is associated with multiple cancers; however, little is known of its role in non-small cell lung cancer (NSCLC). METHODS:The GEPIA, Oncomine and GEO databases were analyzed to assess expression of YTHDC2 in NSCLC patients. Quantitative polymerase chain reaction, western blot and immunohistochemistry were used to detect YTHDC2 expression in different NSCLC cell lines (H1299, H460, H292 and A549) and patients. The effects of YTHDC2 on NSCLC cell lines (A549 and H1299) proliferation and migration were employed using CCK8 and transwell assays. The potential target RNAs of YTHDC2 were obtained from the POSTAR database. Functional enrichment analysis of YTHDC2 targeted RNAs was performed using the Metascape database. RESULTS:GEPIA, Oncomine and GEO databases showed low expression of YTHDC2 in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. YTHDC2 expression was significantly decreased in different NSCLC cell lines and our clinical samples. Moreover, low expression of YTHDC2 was significantly associated with poor differentiation, lymph node metastasis, tumor size and stage. In addition, YTHDC2 could suppress the proliferation and migration ability of A549 and H1299 cell lines. Kaplan-Meier Plotter database analysis revealed that patients with low level of YTHDC2 had a significantly poor prognosis. Finally, functional enrichment analysis of YTHDC2 targeted RNAs indicated several enriched pathways related to cancer. CONCLUSIONS:These findings elucidate that YTHDC2 suppresses tumorigenesis in NSCLC, indicating that YTHDC2 may be a promising therapeutic target for NSCLC. KEY POINTS:SIGNIFICANT FINDINGS OF THE STUDY: This study demonstrated that the downregulation of YTHDC2 promotes tumor progression and predicts poor prognosis in non-small cell lung cancer (NSCLC). WHAT THIS STUDY ADDS:YTHDC2 might be a promising therapeutic target for non-small cell lung cancer (NSCLC).

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

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Dataset Information

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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