REST Promotes Autophagy in Gastric Cancer by Transcriptionally Activating FABP6 to Inhibit the Akt/mTOR Signaling Pathway

Background : Gastric cancer (GC) is a leading cause of cancer -associated death worldwide. Its molecular mechanisms, especially concerning autophagy and various signaling pathways, are not fully understood. Fatty Acid Binding Protein 6 ( FABP6 ) and RE1 Silencing Transcription Factor ( REST ) emerge as potential key players in this context. This study sought to analyze the functional relationship of FABP6 and REST concerning autophagy and their implications on the Akt/mTOR signaling pathway within GC cells. Methods : A comprehensive bioinformatics approach was used to identify key prognostic markers in GC. The effects of FABP6 and REST on autophagy along with Akt/mTOR signaling pathways were analyzed by techniques including Western blotting (WB), flow cytometry, Transwell assay, dual luciferase reporter assay, and others. Results : FABP6 was identified as overexpressed in GC, linked with poor prognosis. FABP6 silencing reduces GC cell proliferation, induces S- and G2 -phase arrest, and downregulates cyclins CDK2 and CDK4. It also inhibited GC cell invasion/migration and autophagy, effects that were counteracted by MG132. When combined with PI3K inhibitor LY294002c, FABP6 knockdown showed synergistic anti -proliferative effects, modulating the Akt/mTOR pathway. Besides, the transcription factor REST has been shown to directly regulate FABP6 expression, affecting autophagy and the Akt/mTOR signaling pathway in a FABP6 -dependent manner. Conclusions : REST positively regulates autophagy and negatively affects the Akt/mTOR signaling pathway in GC cells in a FABP6-dependent manner, providing valuable insights into regulatory networks involving FABP6 and REST .