Work

B3galt5 deficiency attenuates hepatocellular carcinoma by suppressing mTOR/p70s6k-mediated glycolysis

Year: 2022

Type: article

Abstract: Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies with high morbidity and mortality. Beta-1,3-galactosyltransferase 5 (b3galt5) plays crucial roles in protein glycosylation, but its function in HCC remains unclear. Here, we investigated the role and underlying mechanism of b3galt5 in HCC. Methods: B3galt5 expression was measured by western blotting in HCC patient specimens. The role of b3galt5 in hepatocarcinogenesis was determined by cell function assays and diethylnitrosamine (DEN)/TCPOBOP-induced mice HCC models. We performed metabolomics analysis and proteomic sequencing of liver cancer cells from b3galt5-knockdown mice. The glycolysis was detected by Seahorse XF96 extracellular flux analyzer.Results: B3galt5 is highly expressed and associated with a poor prognosis in HCC patients. In vitro studies showed that b3galt5 promoted the proliferation and survival of HCC cells. We also demonstrated that b3galt5 deficiency suppressed hepatocarcinogenesis in DEN/TCPOBOP-induced HCC. Further investigation confirmed that b3galt5 promoted aerobic glycolysis in HCC. Mechanistically, b3galt5 promoted glycolysis by activating the mTOR/p70s6k pathway through N-linked glycosylation modification. Moreover, p70s6k inhibition reduced the expression of key glycolytic enzymes and the glycolysis rate in b3galt5-overexpressing cells. Conclusions: Our study uncovers a novel mechanism by which b3galt5 mediates glycolysis in HCC and highlights the b3galt5-mTOR/p70s6k axis as a potential target for HCC therapy.

Source: Cellular and Molecular Life Sciences

DOI: 10.1007/s00018-022-04601-x