Loss of hepatic FTCD promotes lipid accumulation and hepatocarcinogenesis by upregulating PPARγ and SREBP2

Siying Wang; Yangyang Zhou; Ruobing Yu; Jing Ling; Botai Li; Chen Yang; Zhuoan Cheng; Ruolan Qian; Zhang Lin; Chengtao Yu; Jiaojiao Zheng; Xingling Zheng; Qi Jia; Wei Wu; Qiangxin Wu; Mengnuo Chen; Shengxian Yuan; Wei Dong; Yaoping Shi; Robin Jansen; Chen Yang; Yujun Hao; Ming Yao; Wenxin Qin; Haojie Jin

doi:10.1016/j.jhepr.2023.100843

Loss of hepatic FTCD promotes lipid accumulation and hepatocarcinogenesis by upregulating PPARγ and SREBP2

JHEP Rep. 2023 Jul 12;5(10):100843. doi: 10.1016/j.jhepr.2023.100843. eCollection 2023 Oct.

Authors

Siying Wang¹, Yangyang Zhou¹, Ruobing Yu¹, Jing Ling¹, Botai Li¹, Chen Yang¹, Zhuoan Cheng², Ruolan Qian¹, Zhang Lin¹, Chengtao Yu¹, Jiaojiao Zheng¹, Xingling Zheng¹, Qi Jia¹, Wei Wu¹, Qiangxin Wu¹, Mengnuo Chen¹, Shengxian Yuan³, Wei Dong⁴, Yaoping Shi⁵, Robin Jansen⁶, Chen Yang^{1

7}, Yujun Hao¹, Ming Yao¹, Wenxin Qin¹, Haojie Jin¹

Affiliations

¹ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
⁴ Department of Pathology, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
⁵ Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁶ Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands.
⁷ State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co. Ltd., Nanjing, China.

Abstract

Background & aims: Exploiting key regulators responsible for hepatocarcinogenesis is of great importance for the prevention and treatment of hepatocellular carcinoma (HCC). However, the key players contributing to hepatocarcinogenesis remain poorly understood. We explored the molecular mechanisms underlying the carcinogenesis and progression of HCC for the development of potential new therapeutic targets.

Methods: The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and Genotype-Tissue Expression (GTEx) databases were used to identify genes with enhanced expression in the liver associated with HCC progression. A murine liver-specific Ftcd knockout (Ftcd-LKO) model was generated to investigate the role of formimidoyltransferase cyclodeaminase (FTCD) in HCC. Multi-omics analysis of transcriptomics, metabolomics, and proteomics data were applied to further analyse the molecular effects of FTCD expression on hepatocarcinogenesis. Functional and biochemical studies were performed to determine the significance of loss of FTCD expression and the therapeutic potential of Akt inhibitors in FTCD-deficient cancer cells.

Results: FTCD is highly expressed in the liver but significantly downregulated in HCC. Patients with HCC and low levels of FTCD exhibited worse prognosis, and patients with liver cirrhosis and low FTCD levels exhibited a notable higher probability of developing HCC. Hepatocyte-specific knockout of FTCD promoted both chronic diethylnitrosamine-induced and spontaneous hepatocarcinogenesis in mice. Multi-omics analysis showed that loss of FTCD affected fatty acid and cholesterol metabolism in hepatocarcinogenesis. Mechanistically, loss of FTCD upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element-binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis.

Conclusions: Taken together, we identified a FTCD-regulated lipid metabolic mechanism involving PPARγ and SREBP2 signaling in hepatocarcinogenesis and provide a rationale for therapeutically targeting of HCC driven by downregulation of FTCD.

Impact and implications: Exploiting key molecules responsible for hepatocarcinogenesis is significant for the prevention and treatment of HCC. Herein, we identified formimidoyltransferase cyclodeaminase (FTCD) as the top enhanced gene, which could serve as a predictive and prognostic marker for patients with HCC. We generated and characterised the first Ftcd liver-specific knockout murine model. We found loss of FTCD expression upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element-binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis, and provided a rationale for therapeutic targeting of HCC driven by downregulation of FTCD.

Keywords: Formimidoyltransferase cyclodeaminase; Hepatocarcinogenesis; Lipid metabolism; Tumour suppressor.