Activation of the lipogenic phenotype predicts poor prognosis in human hepatocellular carcinoma

Emerging evidence indicates that lipogenic enzymes are induced in hepatocarcinogenesis, but their role liver cancer development and progression remains poorly delineated. In the present investigation, we determined the levels and biologic role of the main lipogenic enzymes in a human hepatocellular carcinoma (HCC) collection. Levels of Fatty Acid Synthase (FASN), Acetyl-CoA Carboxylase (ACACA), ATP citrate lyase (ACLY), and Steroyl-CoA Desaturase (SCD) were all upregulated in HCC compared with corresponding noncancerous livers. Of note, the highest expression of lipogenic enzymes occurred in tumors with poor prognosis, implying their role in tumor aggressiveness. Suppression of FASN, ACACA, ACLY, and SCD by either siRNA or chemical inhibitors strongly reduced the growth of HCC cells in vitro, leading to massive apoptosis, whereas overexpression of FASN, ACACA, ACLY, and SCD induced a significant increase in proliferation and resistance to chemically-induced apoptosis in HCC cells. At the molecular level, inhibition of FASN was paralleled by downregulation of genes involved in cell proliferation and survival, including Akt, epidermal growth factor receptor (EGFR or ERBB1), S-phase kinase-associated protein 2 (SKP2), and NF- kB, and re-expression of putative oncosuppressor genes, including p21, p27, and death associated protein kinase 2 (DAPK2). Furthermore, FASN expression was regulated at post-transcriptional level by the isopeptidase ubiquitin-specific protease-2a (USP2a), whose suppression resulted in FASN downregulation in HCC cells. Taken together, the present data assign a pathogenetic and prognostic role to deregulation of the fatty acid biosynthetic pathway in liver cancer, and envisage the usefulness of FASN inhibitors as therapeutic modality for human HCC.

Lipogenic phenotype - Fatty Acid Synthase - hepatocellular carcinoma - liver tumor treatment - isopeptidase ubiquitin-specific protease-2a