Sortilin-Driven Cancer Secretome Enhances Tumorigenic Properties of Hepatocellular Carcinoma via de Novo Lipogenesis

Abstract

<p>A growing body of evidence suggests <em>de novo</em> lipogenesis as a key metabolic pathway adopted by cancers to fuel tumorigenic processes. While increased <em>de novo</em> lipogenesis has also been reported in hepatocellular carcinoma (HCC), understanding on molecular mechanisms driving <em>de novo</em> lipogenesis remains limited. In the present study, the functional role of sortilin, a member of the vacuolar protein sorting 10 protein receptor family, in HCC was investigated. Sortilin was overexpressed in HCC and was associated with poorer survival outcome. In functional studies, 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 finding 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 endowed by sortilin-driven cancer secretome were partly abrogated by co-administration of FASN inhibitor C75. Further mechanistic dissection suggested protein stabilization by post-translational modification with <em>O-GlcNAcylation</em> as a major mechanism leading to augmented FASN expression. In conclusion, the present study uncovered the role of sortilin in hepatocarcinogenesis via modulation of the cancer secretome and deregulated lipid metabolism.</p>