BE screen reveals METTL3 S2 dephosphorylation sensitizes gastric cancer cells to oxaliplatin by interfering METTL3-eIF3H interaction
2025-12-12
The resistance to oxaliplatin (OXA)–based chemotherapies may lead to poor prognosis in patients with gastric cancer (GC). Emerging evidence suggests that resistance is closely associated with phosphorylation modifications. In GC cell line AGS, high-throughput base editor screen identified key phosphorylation sites associated with OXA response. Methyltransferase-like 3 (METTL3) S2 emerged as a notable negative hit. Further investigation revealed that dephosphorylation of METTL3 S2 disrupted the METTL3–eukaryotic translation initiation factor 3 subunit H (eIF3H) interaction, thereby suppressing the translation of oncogenes involved in replication stress responses, including bromine domain protein 4 ( BRD4 ) and serpin family E member 2 ( SERPINE2 ), ultimately enhancing sensitivity to OXA. In addition, clinical investigation showed that METTL3 S2 phosphorylation was highly correlated with the response to GC OXA chemotherapy. In summary, base editor screen provides a versatile approach for exploring the role of phosphorylation sites in cancer chemotherapy. The METTL3-eIF3H interaction may serve as a potential therapeutic target.