PRMT1 is a novel molecular therapeutic target for clear cell renal cell carcinoma
文献类型：期刊论文
| 作者 | Wang, Jianfeng1; Wang, Chen2,3; Xu, Pan2,3; Li, Xiao2,3; Lu, Yongning4; Jin, Di1; Yin, Xiaomao1; Jiang, Hao2,3; Huang, Jing2,3; Xiong, Huan5,6 |
| 刊名 | THERANOSTICS
 |
| 出版日期 | 2021 |
| 卷号 | 11期号:11页码:5387-5403 |
| 关键词 | clear cell renal cell carcinoma protein arginine methyltransferase 1 therapeutic lipocalin2 (LCN2) sunitinib |
| ISSN号 | 1838-7640 |
| DOI | 10.7150/thno.42345 |
| 通讯作者 | Luo, Cheng(cluo@simm.ac.cn) ; Huang, Yiran(huangyiran@renji.com) ; Zhang, Yuanyuan(zhangyy@simm.ac.cn) ; Zhang, Jin(med-zhangjin@vip.sina.com) |
| 英文摘要 | Background and Objective: Epigenetic alterations are common events in clear cell renal cell carcinoma (ccRCC), and protein arginine methyltransferase 1 (PRMT1) is an important epigenetic regulator in cancers. However, its role in ccRCC remains unclear. Methods: We investigated PRMT1 expression level and its correlations to clinicopathological factors and prognosis in ccRCC patients based on ccRCC tissue microarrays (TMAs). Genetic knockdown and pharmacological inhibition using a novel PRMT1 inhibitor DCPT1061 were performed to investigate the functional role of PRMT1 in ccRCC proliferation. Besides, we confirmed the antitumor effect of PRMT1 inhibitor DCPT1061 in ccRCC cell-derived tumor xenograft (CDX) models as well as patient-derived tumor xenograft (PDX) models. Results: We found PRMT1 expression was remarkably upregulated in tumor tissues and associated with poor pathologic characters and outcomes of ccRCC patients. Furthermore, genetic knockdown and pharmacological inhibition of PRMT1 by a novel potent inhibitor DCPT1061 dramatically induced G1 cell cycle arrest and suppressed ccRCC cell growth. Mechanistically, RNA sequencing and further validation identified Lipocalin2 (LCN2), a secreted glycoprotein implicated in tumorigenesis, as a crucial regulator of ccRCC growth and functional downstream effector of PRMT1. Epigenetic silencing of LCN2 autocrine secretion by PRMT1 deficiency decreased downstream p-AKT, leading to reduced p-RB and cell growth arrest through the neutrophil gelatinase associated lipocalin receptor (NGALR). Moreover, PRMT1 inhibition by DCPT1061 not only inhibited tumor growth but also sensitized ccRCC to sunitinib treatment in vivo by attenuating sunitinib-induced upregulation of LCN2-AKT-RB signaling. Conclusion: Taken together, our study revealed a PRMT1-dependent epigenetic mechanism in the control of ccRCC tumor growth and drug resistance, indicating PRMT1 may serve as a promising target for therapeutic intervention in ccRCC patients. |
| 资助项目 | National Key R&D Program of China[2017YFB0202600] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[91753000] |
| WOS研究方向 | Research & Experimental Medicine |
| 语种 | 英语 |
| WOS记录号 | WOS:000629071700019 |
| 出版者 | IVYSPRING INT PUBL |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/295341]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Luo, Cheng; Huang, Yiran; Zhang, Yuanyuan; Zhang, Jin |
| 作者单位 | 1.Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Urol, Shanghai 200127, Peoples R China 2.Chinese Acad Sci, CAS Key Lab Receptor Res, State Key Lab Drug Res, Drug Discovery & Design Ctr,Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China 4.Fudan Univ, Zhongshan Hosp, 180 Fenglin Rd, Shanghai 200032, Peoples R China 5.Shanghai Univ, Coll Sci, Dept Chem, 99 Shangda Rd, Shanghai 200444, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 7.Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou 310023, Peoples R China 8.PerkinElmer Management Shanghai Co Ltd, 1670 Zhangheng Rd,Zhandiang High Tech Pk, Shanghai 201203, Peoples R China 9.Shanghai ChemPartner Life Sci Co Ltd, In Vitro Biol, 5 Bldg,998 Halei Rd, Shanghai 201203, Peoples R China 10.Shanghai Inst Technol, Coll Chem & Environm Engn, Shanghai 210032, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Jianfeng,Wang, Chen,Xu, Pan,et al. PRMT1 is a novel molecular therapeutic target for clear cell renal cell carcinoma[J]. THERANOSTICS,2021,11(11):5387-5403. |
| APA | Wang, Jianfeng.,Wang, Chen.,Xu, Pan.,Li, Xiao.,Lu, Yongning.,...&Zhang, Jin.(2021).PRMT1 is a novel molecular therapeutic target for clear cell renal cell carcinoma.THERANOSTICS,11(11),5387-5403. |
| MLA | Wang, Jianfeng,et al."PRMT1 is a novel molecular therapeutic target for clear cell renal cell carcinoma".THERANOSTICS 11.11(2021):5387-5403. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。