Thymidine kinase 1 drives hepatocellular carcinoma in enzyme-dependent and -independent manners

Cell Metab. 2023 Apr 12;S1550-4131(23)00095-5. doi: 10.1016/j.cmet.2023.03.017.

Qing Li ¹, Liren Zhang ¹, Qin Yang ², Mei Li ³, Xiongxiong Pan ⁴, Jiali Xu ⁴, Chen Zhong ¹, Feifan Yao ¹, Ruizhi Zhang ¹, Suiqing Zhou ¹, Xinzheng Dai ¹, Xiaoli Shi ¹, Yongjiu Dai ¹, Jing Xu ⁵, Xu Cheng ⁶, Wenchang Xiao ², Zhigang She ⁶, Ke Wang ⁷, Xiaofeng Qian ⁸, Liyong Pu ⁹, Peng Zhang ¹⁰, Xuehao Wang ¹¹

Affiliations

1 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China.
2 Department of Cardiovascular Surgery, Huanggang Central Hospital, Huanggang Institute of Translational Medicine, Huanggang, China.
3 School of Basic Medical Science, Wuhan University, Wuhan, China.
4 Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
5 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
6 School of Basic Medical Science, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China; Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
7 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China. Electronic address: [email protected].
8 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China. Electronic address: [email protected].
9 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China. Electronic address: [email protected].
10 School of Basic Medical Science, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China; Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China. Electronic address: [email protected].
11 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China. Electronic address: [email protected].

PMID: 37071992 DOI: 10.1016/j.cmet.2023.03.017

Abstract

Metabolic reprogramming plays a crucial role in the development of hepatocellular carcinoma (HCC). However, the key drivers of metabolic reprogramming underlying HCC progression remain unclear. Using a large-scale transcriptomic database and survival correlation screening, we identify thymidine kinase 1 (TK1) as a key driver. The progression of HCC is robustly mitigated by TK1 knockdown and significantly aggravated by its overexpression. Furthermore, TK1 promotes the oncogenic phenotypes of HCC not only through its enzymatic activity and production of deoxythymidine monophosphate (dTMP) but also by promoting glycolysis via binding with protein arginine methyltransferase 1 (PRMT1). Mechanistically, TK1 directly binds PRMT1 and stabilizes it by interrupting its interactions with tripartite-motif-containing 48 (TRIM48), which inhibits its ubiquitination-mediated degradation. Subsequently, we validate the therapeutic capacity of hepatic TK1 knockdown in a chemically induced HCC mouse model. Therefore, targeting both the enzyme-dependent and -independent activity of TK1 may be therapeutically promising for HCC treatment.

Keywords

DNA methylation; PRMT1; hepatocellular carcinoma; metabolic reprogramming; ubiquitination.

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