Increased Lipogenesis, Induced by AKT-mTORC1-RPS6 Signaling, Promotes Development of Human Hepatocellular Carcinoma

Abstract

Background & Aims De novo lipogenesis is believed to be involved in oncogenesis. We investigated the role of aberrant lipid biosynthesis in pathogenesis of human hepatocellular carcinoma (HCC). Methods We evaluated the expression of enzymes that regulate lipogenesis in human normal liver tissues and HCC and surrounding, non-tumor, liver tissues from patients using real-time reverse transcription PCR, immunoblotting, immunohistochemistry, and biochemical assays. Effects of lipogenic enzymes on human HCC cell lines were evaluated using inhibitors and overexpression experiments. The lipogenic role of the proto-oncogene AKT was assessed in vitro and in vivo. Results In human liver samples, de novo lipogenesis was progressively induced from non-tumorous liver tissue toward the HCC. The extent of aberrant lipogenesis correlated with clinical aggressiveness, activation of the AKT–mTOR signaling pathway, and suppression of AMP-activated protein kinases. In HCC cell lines, the AKT–mTORC1–RPS6 pathway promoted lipogenesis via transcriptional and post-transcriptional mechanisms that included inhibition of FASN ubiquitination by the USP2a de-ubiquitinase and disruption of the SREBP1 and SREBP2 degradation complexes. Suppression of the genes ACLY, ACAC, FASN, SCD1, or SREBP1, which are involved in lipogenesis, reduced proliferation and survival of HCC cell lines and AKT-dependent cell proliferation. Overexpression of an activated form of AKT in livers of mice induced lipogenesis and tumor development. Conclusions De novo lipogenesis has pathogenic and prognostic significance for HCC. Inhibitors of lipogenic signaling, including those that inhibit the AKT pathway, might be useful as therapeutics for patients with liver cancer.