Rev-erbα is a nuclear receptor, which regulates circadian rhythm, inflammatory responses and lipid metabolism. We previously showed Rev-erbα reduction in human gastric cancer, which is associated with TMN stages and poor prognosis. We hypothesized that Rev-erbα modulates proliferation via glycolytic flux and the pentose phosphate pathway (PPP) in gastric cancer. Knockdown of Rev-erbα significantly increased proliferation as well as glycolytic flux and the PPP in human gastric cancer cells. These effects were reduced by a Rev-erbα agonist GSK4112 in a dose-dependent manner. Furthermore, Rev-erbα 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-erbα 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-erbα compared to the patients with high expression of Rev-erbα. In conclusion, Rev-erbα reduction causes gastric cancer progression by augmenting the PPP and glycolysis.

Rev-erbα是一种核受体，可调节昼夜节律，炎症反应和脂质代谢。我们先前显示人类胃癌的Rev-erbα减少，这与TMN分期和不良预后有关。我们假设Rev-erbα通过糖酵解通量和戊糖磷酸途径（PPP）调节胃癌的增殖。敲除Rev-erbα可以显着增加人胃癌细胞的增殖以及糖酵解通量和PPP。Rev-erbα激动剂GSK4112以剂量依赖的方式降低了这些作用。此外，Rev-erbα被募集到PFKFB3和G6PD基因的启动子上，从而抑制了它们的基因转录。GSK4112处理降低了PFKFB3和G6PD基因的表达，这不受BMAL1敲低的影响。使用相应的PFKFB3和G6PD抑制剂对糖酵解和PPP的药理学抑制作用减弱了Rev-erbα基因敲低诱导的胃癌细胞增殖。GSK4112处理不能减少SGC-7901过表达PFKFB3和G6PD基因的增殖。PFKFB3和G6PD在胃癌患者中均过表达，并且与TMN分期呈正相关。与高表达Rev-erbα的患者相比，低表达Rev-erbα的患者的胃癌组织中的PPP和糖酵解得到增强。总之，Rev-erbα的降低通过增加PPP和糖酵解而导致胃癌的进展。GSK4112处理不能减少SGC-7901过表达PFKFB3和G6PD基因的增殖。PFKFB3和G6PD在胃癌患者中均过表达，并且与TMN分期呈正相关。与高表达Rev-erbα的患者相比，低表达Rev-erbα的患者的胃癌组织中的PPP和糖酵解得到增强。总之，Rev-erbα的降低通过增加PPP和糖酵解而导致胃癌的进展。GSK4112处理不能减少SGC-7901过表达PFKFB3和G6PD基因的增殖。PFKFB3和G6PD在胃癌患者中均过表达，并且与TMN分期呈正相关。与高表达Rev-erbα的患者相比，低表达Rev-erbα的患者的胃癌组织中的PPP和糖酵解得到增强。总之，Rev-erbα的降低会通过增加PPP和糖酵解而导致胃癌的进展。