SHMT2 Promotes Gastric Cancer Development through Regulation of HIF1α/VEGF/STAT3 Signaling

Abstract

The metabolic enzymes involved in one-carbon metabolism are closely associated with tumor progression and could be potential targets for cancer therapy. Recent studies showed that serine hydroxymethyltransferase 2 (SHMT2), a crucial enzyme in the one-carbon metabolic pathway, plays a key role in tumor proliferation and development. However, the precise role and function of SHMT2 in gastric cancer (GC) remain poorly understood. In this study, we presented evidence that SHMT2 was necessary for hypoxia-inducible factor-1α (HIF1α) stability and contributed to GC cells’ hypoxic adaptation. The analysis of datasets retrieved from The Cancer Genome Atlas and the experimentation with human cell lines revealed a marked increase in SHMT2 expression in GC. The SHMT2 knockdown in MGC803, SGC7901, and HGC27 cell lines inhibited cell proliferation, colony formation, invasion, and migration. Notably, SHMT2 depletion disrupted redox homeostasis and caused glycolytic function loss in GC cells under hypoxic circumstances. Mechanistically, we discovered SHMT2 modulated HIF1α stability, which acted as a master regulator of hypoxia-inducible genes under hypoxic conditions. This, in turn, regulated the downstream VEGF and STAT3 pathways. The in vivo xenograft experiments showed that SHMT2 knockdown markedly reduced GC growth. Our results elucidate the novel function of SHMT2 in stabilizing HIF1α under hypoxic conditions, thus providing a potential therapeutic strategy for GC treatment.

Phosphorylated SHMT2 Regulates Oncogenesis Through m6A Modification in Lung Adenocarcinoma

“…SHMT2 overexpression promotes cancer cell proliferation, invasion and tumorigenesis, and knocking down SHMT2 inhibits tumor progression. [ 11 , 12 , 13 , 14 ] SHMT2‐mediated mitochondrial serine metabolism was also reported to drive the drug resistance of cancer cells. [ 15 ] SHMT2 regulates the methylation of mitochondrial tRNA and mediates the translation of respiratory chain proteins by providing one‐carbon units.…”

Comparative study on the expression of Pax3, Rad51 and VEGF-C in esophageal gastric junction adenocarcinoma and distal gastric adenocarcinoma

“…Studies have underscored the multifaceted nature of AEJ's etiology, emphasizing the interplay of various factors within the body [2]. Unraveling the intricate network of interactions that contribute to the genesis and progression of this specialized gastric cancer subtype is crucial for devising targeted therapeutic strategies.…”