N7-Methylguanine Modification of SHMT2 Mediated by GEMIN5 Inhibits Cell Ferroptosis of Colorectal Cancer Cells

Colorectal Cancer (CRC) is a common malignancy in the digestive tract. Serine hydroxymethyltransferase 2 (SHMT2) plays a critical role in CRC progression, and its regulatory mechanisms warrant further investigation. The regulatory role of SHMT2 was investigated by assessing cell viability and Ferroptosis. RNA methylation detection was performed to determine the predominant methylation modification types. The interaction between GEMIN5 (which binds to the m⁷G cap) was analyzed through RNA immunoprecipitation (RIP) and dual luciferase reporter assays. Finally, the synergistic regulation of GEMIN5 and SHMT2 on the Wnt/β-catenin signaling pathway was examined. SHMT2 was highly expressed in CRC tissues, and its inhibition suppressed cell viability while promoting Ferroptosis. Quantitative analysis revealed significantly elevated m⁷G levels in CRC cells. GEMIN5 expression positively correlated with SHMT2 levels in CRC, and GEMIN5 overexpression increased m⁷G modification levels of SHMT2 mRNA. RIP assays demonstrated that SHMT2 mRNA could be enriched in GEMIN5 complexes, with GEMIN5 overexpression inhibiting SHMT2 mRNA degradation. SHMT2 overexpression counteracted the effects of GEMIN5 knockdown, while GEMIN5 overexpression prominently reversed the regulatory effects of SHMT2 knockdown on β-catenin and GSK3β protein expression. GEMIN5-mediated m⁷G modification stabilizes high SHMT2 expression, which inhibits CRC cell Ferroptosis and activates the Wnt/β-catenin signaling pathway in vitro.

GEMIN5; SHMT2; Wnt/β‐catenin; colorectal cancer; ferroptosis; m7G.