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Multi-omics analysis reveals RNA polymerase II degradation as a novel mechanism of PF-3758309's anti-tumor activity

文献类型：期刊论文

作者Jia, Xinglong2,3; Zhang, Jingdan4,5; Pan, Lulu6; He, Jingliang7; Zhu, Mingrui3; Zhao, Lei1,8; Zhang, Xingyu7; Zhao, Wensi9; Xie, Dong9; Shen, Xiaoyan2
刊名CELL DEATH DISCOVERY
出版日期2025-08-25
卷号11期号:1页码:13
DOI10.1038/s41420-025-02677-5
英文摘要PF-3758309, a pyrrolopyrimidine-based inhibitor of p21-activated kinase 4 (PAK4), has demonstrated preclinical anti-tumor activity. However, due to poor pharmacokinetics and off-target effects, it has not advanced to clinical use. In this study, we conducted a comprehensive multi-omics analysis, including proteomics, transcriptomics, and ubiquitinomics, to investigate the mechanism of PF-3758309 in HCT116 cells. Our results revealed that PF-3758309 promotes the degradation of RNA polymerase II subunit proteins (POLR2A/B/E) via the cullin-RING ligase pathway. This process is mediated by the E3 ubiquitin ligase DNA damage-binding protein 2 (DDB2), and is independent of PAK4. Furthermore, the small-molecule inhibitor MLN4924, which blocks NEDD8-activating enzyme, reversed the degradation of POLR2A/B/E, supporting the role of ubiquitin-proteasome pathways in this process. Functional assays confirmed that PF-3758309 inhibits tumor cell growth and migration by promoting ubiquitination-dependent degradation of POLR2A/B/E. These findings uncover a previously unrecognized mechanism of PF-3758309's anti-tumor activity and provide a basis for further investigation into its therapeutic potential.
WOS关键词LUNG-CANCER ; INHIBITOR ; P53
资助项目National Key Research and Development Program of China[2023YFA1800400] ; National Natural Science Foundation of China[22225702] ; National Natural Science Foundation of China[U24A20524] ; National Natural Science Foundation of China[82273167] ; Program of Shanghai Academic Research Leader[22XD1420900] ; Innovative Research Team of High-Level Local Universities in Shanghai[SHSMUZDCX20212700] ; Guangdong High-level Innovative Research Institute, China[2021B0909050003] ; Jiangsu Province Basic Research Program Natural Science Foundation (Outstanding Youth Fund Project)[BK20220063] ; Program of Basic Science (Natural Science) of Jiangsu Province[22KJA350001]
WOS研究方向Cell Biology
语种英语
WOS记录号WOS:001556619200003
出版者SPRINGERNATURE
源URL[http://119.78.100.183/handle/2S10ELR8/321312]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Shen, Xiaoyan; Liu, Bin; Tan, Minjia
作者单位1.Tongji Univ, Canc Ctr, Sch Med, Shanghai, Peoples R China
2.Fudan Univ, Sch Pharm, Shanghai, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
4.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou, Peoples R China
5.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Peoples R China
6.Zhengzhou Univ, Cent China Fuwai Hosp, Henan Prov Peoples Hosp, Dept Pharm, Zhengzhou, Henan, Peoples R China
7.Jiangsu Ocean Univ, Coll Pharm, Jiangsu Key Lab Marine Pharmaceut Cpd Screening, Lianyungang, Peoples R China
8.Tongji Univ, Shanghai Peoples Hosp 4, Translat Res Inst Brain & Brain Like Intelligence, Shanghai, Peoples R China
9.Tongji Univ, Shanghai Pulm Hosp, Sch Med, Dept Thorac Surg, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Jia, Xinglong,Zhang, Jingdan,Pan, Lulu,et al. Multi-omics analysis reveals RNA polymerase II degradation as a novel mechanism of PF-3758309's anti-tumor activity[J]. CELL DEATH DISCOVERY,2025,11(1):13.
APA Jia, Xinglong.,Zhang, Jingdan.,Pan, Lulu.,He, Jingliang.,Zhu, Mingrui.,...&Tan, Minjia.(2025).Multi-omics analysis reveals RNA polymerase II degradation as a novel mechanism of PF-3758309's anti-tumor activity.CELL DEATH DISCOVERY,11(1),13.
MLA Jia, Xinglong,et al."Multi-omics analysis reveals RNA polymerase II degradation as a novel mechanism of PF-3758309's anti-tumor activity".CELL DEATH DISCOVERY 11.1(2025):13.

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来源：上海药物研究所

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