SORTILIN-DRIVEN CANCER SECRETOME ENHANCES TUMORIGENIC PROPERTIES OF HEPATOCELLULAR CARCINOMA VIA DE NOVO LIPOGENESIS.

A growing body of evidence suggests de novo lipogenesis (DNL) as a key metabolic pathway adopted by cancers to fuel tumorigenic processes. While increased DNL has also been reported in hepatocellular carcinoma (HCC), understanding on molecular mechanisms driving DNL remains limited. In the present study, we investigated the functional role of sortilin, a member of the vacuolar protein sorting 10 protein (Vps10p) receptor family, in HCC. Sortilin was overexpressed in HCC and associated with poorer survival outcome. Functional studies showed that sortilin-overexpressing cells conferred tumorigenic phenotypes namely, self-renewal and metastatic potential, of HCC cells via the cancer secretome. Proteomic profiling highlighted fatty acid metabolism as a potential molecular pathway associated with sortilin-driven cancer secretome. This was validated by the increased lipid content and expression of fatty acid synthase (FASN) in HCC cells treated with conditioned medium collected from sortilin-overexpressing cells. The enhanced tumorigenic properties endowered by sortilin-driven cancer secretome were partly abrogated by co-administration of FASN inhibitor C75. Further mechanistic dissection suggested protein stabilization by O-GlcNAcylation as a major mechanism leading to augmented FASN expression. In conclusion, our study uncovered the role of sortilin in contributing to hepatocarcinogenesis via modulation of the cancer secretome and deregulated lipid metabolism.