Aberrant Expression of Citrate Synthase is Linked to Disease Progression and Clinical Outcome in Prostate Cancer

Zhiduan Cai,1,* Yulin Deng,1,* Jianheng Ye,2 Yangjia Zhuo,3 Zezhen Liu,2 Yingke Liang,3 Hui Zhang,3 Xuejin Zhu,2 Yong Luo,3 Yuanfa Feng,4 Ren Liu,2 Guo Chen,5 Yongding Wu,3 Zhaodong Han,3 Yuxiang Liang,3 Funeng Jiang,3 Weide Zhong1– 4,6 1Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People’s Republic of China; 2Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou 510180, People’s Republic of China; 3Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, People’s Republic of China; 4Urology Key Laboratory of Guangdong Province, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510230, People’s Republic of China; 5Department of Urology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, People’s Republic of China; 6School of Medicine, Jinan University, Guangzhou, Guangdong 510632, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weide ZhongGuangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People’s Republic of ChinaEmail zhongwd2009@live.cnPurpose: Citrate synthase (CS) is a rate-limiting enzyme in the citrate cycle and is capable of catalyzing oxaloacetate and acetyl-CoA to citrate. CS has been uncovered to be upregulated in a variety of cancers, and its expression and clinical significance in prostate cancer (PCa) remain unknown.Methods: In this study, we examined the association between CS expression level and clinicopathological features of prostate cancer patients in a TMA cohort and the public cancer database (The Cancer Genome Atlas-Prostate Adenocarcinoma, TCGA-PRAD). The CS knockdown cell lines were constructed to study the effects of CS downregulation on proliferation, colony formation, migration, invasion, and cell cycle of prostate cancer cells in vitro. And the effect of CS downregulation on tumor growth in mice was studied in vivo. In addition, the metabolomics and mitochondrial function were detected in the CS knockdown cell lines.Results: CS expression level in PCa tissues was higher than that in normal tissues (P < 0.05). CS upregulation was significantly associated with high Gleason score (P < 0.05), advanced pathological stage (P < 0.001), and biochemical recurrence (P < 0.001). Functionally, decreased expression of CS inhibited PCa cell proliferation, colony formation, migration, invasion and cell cycle in vitro, and inhibited tumor growth in vivo. In addition, CS downregulation exerted potential inhibitory effects on the lipid metabolism and mitochondrial function of PCa cells.Conclusion: In conclusion, these findings suggested that CS upregulation may contribute to the aggressive progression and poor prognosis of PCa patients, which might be partially associated with its influences on the cell lipid metabolism and mitochondrial function.Keywords: prostate cancer, citrate synthase, prognosis, lipid metabolism