Che, Li and Chi, Wenna and Qiao, Yu and Zhang, Jie and Song, Xinhua and Liu, Ye and Li, Lei and Jia, Jiaoyuan and Pilo, Maria G. and Wang, Jingxiao and Cigliano, Antonio and Ma, Zhilong and Kuang, Wenhua and Tang, Zefang and Zhang, Zemin and Shui, Guanghou and Ribback, Silvia and Dombrowski, Frank and Evert, Matthias and Pascale, Rosa Maria and Cossu, Carla and Pes, Giovanni Mario and Osborne, Timothy F. and Calvisi, Diego F. and Chen, Xin and Chen, Ligong (2020) Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans. GUT, 69 (1). pp. 177-186. ISSN 0017-5749, 1468-3288
Full text not available from this repository. (Request a copy)Abstract
Objective Increased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC). Design We investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specific Fasn knockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type and Fasn knockout mice. Human HCC cell lines were used for in vitro studies. Results Ablation of Fasn significantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged in Fasn knockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss of Fasn promoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 (dnSrebp2) completely prevented sgPten/c-Met driven hepatocarcinogenesis in Fasn knockout mice. Similarly, silencing of FASN resulted in increased SREBP2 activation and hydroxy-3-methyl-glutaiyl-CoA (HMG-CoA) reductase (HMGCR) expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture. Conclusion Our study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACTIVATES PPAR-ALPHA; CELL-CYCLE ARREST; HEPATOCELLULAR-CARCINOMA; CANCER; LIVER; TRANSCRIPTION; APOPTOSIS; REDUCTASE; STATINS; GLUCOSE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Apr 2021 09:30 |
| Last Modified: | 08 Apr 2021 09:30 |
| URI: | https://pred.uni-regensburg.de/id/eprint/45547 |
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