Hypoxia-induced FOXO4/LDHA axis modulates gastric cancer cell glycolysis and progression

Background and aim We previously identified forkhead box (FOX) O4 mRNA as a predictor in gastric cancer (GC). However, the underlying mechanism has yet to be elucidated. We aimed to illustrate the mechanism by which FOXO4 regulated glycolysis under hypoxia in GC. Methods FOXO4 protein expression was investigated by immunohistochemical staining of 252 GC and their normal adjacent tissues. We restored or silenced FOXO4 expression in GC cell lines to explore the underlying mechanisms. Results FOXO4 was downregulated in GC. Loss of FOXO4 expression was validated in univariate and multivariate survival analysis as an independent prognostic predictor for overall survival (P < 0.05) and disease-free survival (P<0.05). Restored FOXO4 expression significantly impaired the glycolysis rate in GC cells, while silencing FOXO4 expression enhanced glycolysis rate. FOXO4 expression was inversely associated with maximum standardized uptake value in mice models and patient samples. Mechanistically, FOXO4 bound to the glycolytic enzyme lactate dehydrogenase (LDH)A promoter and inactivated its activity in a dose-dependent manner (P < 0.05). Finally, we determined that FOXO4 was a transcriptional target of hypoxia-inducible factor (HIF) -1 alpha, which is central in response to hypoxia. Conclusions Our data suggested that FOXO4 plays a key role in the regulation of glycolysis in GC, and disrupting the HIF-1 alpha-FOXO4-LDHA axis might be a promising therapeutic strategy for GC.

Automated summary

FOXO4 downregulation in gastric cancer is associated with poor prognosis. Restoring FOXO4 expression decreases glycolysis rate in GC cells, while silencing it increases glycolysis rate. FOXO4 is a transcriptional target of HIF-1 alpha and plays a key role in regulating glycolysis in GC.