Tumor-intrinsic PRMT5 upregulates FGL1 via methylating TCF12 to inhibit CD8+ T-cell-mediated antitumor immunity in liver cancer.
10.1016/j.apsb.2024.10.016
- Author:
Jiao SUN
1
;
Hongfeng YUAN
1
;
Linlin SUN
1
;
Lina ZHAO
1
;
Yufei WANG
1
;
Chunyu HOU
1
;
Huihui ZHANG
1
;
Pan LV
1
;
Guang YANG
1
;
Ningning ZHANG
2
;
Wei LU
2
;
Xiaodong ZHANG
1
Author Information
1. State Key Laboratory of Drug ability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer/Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
2. Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin 300060, China.
- Publication Type:Journal Article
- Keywords:
Antitumor immunity;
FGL1;
Liver cancer;
PRMT5;
TCF12
- From:
Acta Pharmaceutica Sinica B
2025;15(1):188-204
- CountryChina
- Language:English
-
Abstract:
Protein arginine methyltransferase 5 (PRMT5) acts as an oncogene in liver cancer, yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined. Here, we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8+ T-cell-mediated antitumor immunity both in vivo and in vitro. Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule, fibrinogen-like protein 1 (FGL1). Mechanistically, PRMT5 catalyzed symmetric dimethylation of transcription factor 12 (TCF12) at arginine 554 (R554), prompting the binding of TCF12 to FGL1 promoter region, which transcriptionally activated FGL1 in tumor cells. Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression, which promoted CD8+ T-cell-mediated antitumor immunity. Notably, combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice. Collectively, our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.
