Downregulation of FABP5 suppresses mTOR -mediated autophagy via an increase in FASN to promote colorectal cancer progression

Abstract

BackgroundLipid metabolism plays an important role in the occurrence and development of cancer, in particular, digestive system tumors such as colon cancer. Here, we investigated the role of the fatty acid-binding protein 5 (FABP5) in colorectal cancer(CRC). MethodsTo this end, tissue microarray was initially used for analysis of FABP5 expression, followed by generation of stable cell lines with knockdown or overexpression of FABP5 for a series of functional assays including CCK-8, colony formation, EdU and transwell experiments. Co-IP, RNA-seq and omics-based lipid metabolism studies were further performed to explore the mechanisms of action of FABP5 in CRC. The function of FABP5 in vivo was analyzed with the aid of tumor xenograft and immunohistochemistry experiments. ResultsWe observed marked downregulation of FABP5 in CRC. Data from functional assays revealed inhibitory effects of FABP5 on cell proliferation, colony formation, migration, invasion as well as tumor growth in vivo. In terms of mechanistic insights, FABP5 interacted with fatty acid synthase (FASN) and activated the ubiquitin proteasome pathway, leading to a decrease in FASN expression and lipid accumulation, in turn, suppressing mTOR signaling and facilitating cell autophagy. Orlistat, a FASN inhibitor, exerted anticancer effects both in vivo and in vitro. Moreover, the upstream RNA demethylase ALKBH5 positively regulated FABP5 expression via an m 6 A-independent mechanism. ConclusionOur collective ndings offer valuable insights into the critical role of the FABP5/FASN axis in tumor progression and uncover a potential mechanism linking lipid metabolism to development of CRC, providing novel therapeutic targets for future interventions.