LACTB inhibits lipid synthesis to suppress glioma growth by promoting Hsc70-mediated ERBB3 degradation

Abnormal lipid metabolism is a hallmark of tumor and represents an anti-cancer strategy. ß-lactamase like protein (LACTB) is a novel tumor suppressor, but the biological function and the involved mechanism in glioma remain unclear. Here, we show that LACTB overexpression suppresses glioma growth while LACTB knockdown shows the opposite effect. By RNA-sequencing and untargeted lipidomics analysis, we find that LACTB overexpression inhibits the lipid synthesis of glioma cells. Mechanistically, LACTB downregulates ERBB3 and inhibits PI3K/AKT/mTOR signaling, which restrains the lipogenesis of tumor cells. We further uncover that LACTB overexpression decreases the protein stability of ERBB3 by lysosomal degradation. LACTB promotes the interaction of ERBB3 and Hsc70 to facilitate ERBB3 degradation in lysosome. Finally, we show that targeting LACTB/ERBB3 axis significantly suppresses glioma growth in the mouse model. Therefore, our study reveals the antitumoral role of LACTB in glioma and the LACTB/ERBB3 axis represents a potential new therapeutic target for this tumor. Overall design: LN229 cells transduced with vector or LACTB were subject to RNA-seq to identify the differentially expressed genes and perform function enrichment analysis. The main goal of the RNA-seq is to reveal the biological function of LACTB on glioma cells.