Epitranscriptomic Regulation of ALDOA by SHMT2-Mediated m6A Modification Drives Gastric Cancer Malignancy.

Abstract

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited therapeutic advancements despite progress in early detection. Serine hydroxymethyltransferase 2 (SHMT2), a key metabolic enzyme, and fructose-1,6-bisphosphate aldolase A (ALDOA), a glycolytic enzyme, are implicated in tumor progression. However, the molecular mechanisms linking SHMT2 and ALDOA in GC remain unclear. This study investigates how SHMT2 regulates ALDOA expression via m6A RNA modification to drive GC malignancy. Bioinformatic analyses (TCGA, LinkedOmics, and SRAMP) were used to assess SHMT2 expression in GC patients and identify its correlated genes. In vitro experiments (CCK-8, EdU, Transwell, and wound healing) evaluated the effects of SHMT2 overexpression or knockdown on GC cell proliferation, migration, invasion, and glycolysis. m6A modification of ALDOA was analyzed via MeRIP-PCR and dual-luciferase assays, while RNA stability was assessed using actinomycin D treatment. Xenograft models validated SHMT2's role in vivo. SHMT2 was upregulated in GC tissues and cell lines, correlating with advanced tumor stages and poor prognosis. SHMT2 knockdown suppressed GC cell viability, migration, invasion, and glycolysis, while overexpression enhanced these traits. Mechanistically, SHMT2 increased S-adenosylmethionine levels, promoting ALDOA m6A modification, likely mediated through the predicted site 1 (position 291). This modification stabilized ALDOA mRNA via IGF2BP1 recognition, an m6A reader. ALDOA overexpression reversed the tumor-suppressive effects of SHMT2 knockdown. In vivo, SHMT2 depletion reduced tumor growth and Ki67 expression in xenograft models. In conclusion, SHMT2 drives GC progression by enhancing ALDOA expression through m6A modification and IGF2BP1-mediated stabilization. Targeting the SHMT2-ALDOA axis represents a promising therapeutic strategy for gastric cancer.