Rev-erbα inhibits proliferation by reducing glycolytic flux and pentose phosphate pathway in human gastric cancer cells

Rev-erb alpha is a nuclear receptor, which regulates circadian rhythm, inflammatory responses and lipid metabolism. We previously showed Rev-erb alpha reduction in human gastric cancer, which is associated with TMN stages and poor prognosis. We hypothesized that Rev-erb alpha modulates proliferation via glycolytic flux and the pentose phosphate pathway (PPP) in gastric cancer. Knockdown of Rev-erb alpha significantly increased proliferation as well as glycolytic flux and the PPP in human gastric cancer cells. These effects were reduced by a Rev-erb alpha agonist GSK4112 in a dose-dependent manner. Furthermore, Rev-erb alpha was recruited on the promoters of PFKFB3 and G6PD genes, thereby inhibiting their gene transcription. GSK4112 treatment reduced PFKFB3 and G6PD gene expression, which was not affected by BMAL1 knockdown. Pharmacological inhibition of glycolysis and the PPP using corresponding PFKFB3 and G6PD inhibitors attenuated Rev-erb alpha knockdown-induced proliferation in gastric cancer cells. GSK4112 treatment was not able to reduce proliferation in SGC-7901 overexpressing both PFKFB3 and G6PD genes. Both PFKFB3 and G6PD were overexpressed in patients with gastric cancer, and positively correlated with the TMN stages. The PPP and glycolysis were enhanced in gastric cancer tissues of patients with low expression of Rev-erb alpha compared to the patients with high expression of Rev-erb alpha. In conclusion, Rev-erb alpha reduction causes gastric cancer progression by augmenting the PPP and glycolysis.