Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans

Abstract

Background & Aims Cumulating evidence underlines the crucial role of aberrant lipogenesis in human hepatocellular carcinoma (HCC). Here, we investigated the oncogenic potential of fatty acid synthase (FASN), the master regulator of de novo lipogenesis, in the mouse liver. Methods FASN was overexpressed in the mouse liver, either alone or in combination with activated N-Ras, c-Met, or SCD1, via hydrodynamic injection. Activated AKT was overexpressed via hydrodynamic injection in livers of conditional FASN or Rictor knockout mice. FASN was suppressed in human hepatoma cell lines via specific small interfering RNA. Results Overexpression of FASN, either alone or in combination with other genes associated with hepatocarcinogenesis, did not induce histological liver alterations. In contrast, genetic ablation of FASN resulted in the complete inhibition of hepatocarcinogenesis in AKT-overexpressing mice. In human HCC cell lines, FASN inactivation led to a decline in cell proliferation and a rise in apoptosis, which were paralleled by a decrease in the levels of phosphorylated/activated AKT, an event controlled by the mammalian target of rapamycin complex 2 (mTORC2). Downregulation of AKT phosphorylation/activation following FASN inactivation was associated with strong inhibition of rapamycin-insensitive companion of mTOR (Rictor), the major component of mTORC2, at post-transcriptional level. Finally, genetic ablation of Rictor impaired AKT-driven hepatocarcinogenesis in mice. Conclusions FASN is not oncogenic per se in the mouse liver, but is necessary for AKT-driven hepatocarcinogenesis. Pharmacological blockade of FASN might be highly useful in the treatment of human HCC characterized by activation of the AKT pathway.

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

“…33 To investigate whether FASN expression is required for myr-AKT driven liver tumor development, we hydrodynamically transfected myr-AKT and Cre recombinase (AKT/Cre mice) into FASN fl/fl mice. 37 Strikingly, while AKT overexpression in control mice led to malignant liver tumor formation by 22-28 weeks post-injection, in accordance with previous findings, 33 none of the AKT/Cre mice exhibited either liver enlargement or increased liver weight. Histologically, most of the liver parenchyma of AKT control mice was occupied by multiple hepatocellular tumors, whereas none of AKT/ Cre mice displayed preneoplastic and neoplastic lesions.…”

“…However, overexpression of FASN in the liver, either alone or in combination with other putative oncogenes, such as activated N-Ras or c-Met, does not trigger tumor formation in mice. 37 Consistently, liver-specific SREBP1C and SERPB1a transgenic mice showed an increased lipid biosynthesis paralleled by the upregulation of FASN, ACC and SCD1, leading to hepatic steatosis, 38 but no liver tumor development. Together, the results suggest that FASN and its mediated de novo lipogenesis are not oncogenic per se.…”

“…At the molecular level, we found that ablation of FASN in AKT/Cre mice resulted in decreased protein expression of Rictor (rapamycin-insensitive companion of mTOR), the main component of the mammalian target of rapamycin complex 2 (mTORC2), leading to the downregulation of phosphorylated/activated AKT. 37 The critical role of Rictor/mTORC2 in mediating activated AKT driven hepatocarcinogenesis was further validated using conditional Rictor fl/fl mice. 37 Specifically, ablation of Rictor in hepatocytes prevented myr-AKT driven hepatocarcinogenesis in mice, recapitulating the phenotypes observed in conditional FASN KO mice.…”

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

“…Blocking lipogenesis is a potential strategy for targeted therapy of HCC (Calvisi et al ., 2011). Genetic ablation of lipogenic enzymes results in complete inhibition of HCC development in mice with an AKT overexpression background (Li et al ., 2016a). Targeted treatment options for HCC are limited.…”

“…Overexpression of lipogenic enzymes is closely related with hepatocarcinogenesis (Hu et al ., 2016; Li et al ., 2016a). These lipogenic enzymes are primarily transcriptionally activated by sterol regulatory element binding protein (SREBP) (Goldstein et al ., 2006).…”