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

Background & AimsCumulating 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.MethodsFASN 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.ResultsOverexpression 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.ConclusionsFASN 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.List of Abbreviations: ACAC, acetyl-CoA carboxylase; ACLY, adenosine triphosphate citrate lyase; AKT, v-akt murine thymoma viral oncogene homolog; ELOVL5, elongation of very long chain fatty acids protein 5; FASN, fatty acid synthase; HCC, hepatocellular carcinoma; LDH, lactate dehydrogenase; mTOR, mammalian target of rapamycin; mTORC, mTOR complex; N-Ras, neuroblastoma Ras viral oncogene homolog; PKM2, pyruvate kinase M2 isoform; Raptor, regulatory-associated protein of mTOR; Rictor, rapamycin-insensitive companion of mTOR; Rps6, ribosomal protein S6; Scd1, stearoyl-CoA desaturase 1; siRNA, small interfering RNA.KeywordsHepatocellular carcinoma; Lipogenesis; Fatty acid synthase; AKT; Rictor