Arginine methyltransferase PRMT5 methylates and stabilizes KLF5 via decreasing its phosphorylation and ubiquitination to promote basal-like breast cancer
机构：[1]Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China[2]KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Kunming, Yunnan, China[3]Kunming College of Life Sciences, University of Chinese Academy Sciences, Kunming, Yunnan, China[4]Department of Pathology, The First Affiliated Hospital, Kunming Medical University, Kunming, China昆明医科大学附属第一医院[5]Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA[6]School of Pharmaceutical Science, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China[7]The First Affiliated Hospital, Peking University, Beijing, China[8]School of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, Yunnan, China[9]Department of Pathology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China[10]State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China[11]Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
Kruppel-like factor 5 (KLF5) is an oncogenic factor that is highly expressed in basal-like breast cancer (BLBC) and promotes cell proliferation, survival, migration, stemness, and tumor growth; however, its posttranslational modifications are poorly defined. Protein arginine methyltransferase 5 (PRMT5) is also an oncogene implicated in various carcinomas, including breast cancer. In this study, we found that PRMT5 interacts with KLF5 and catalyzes the di-methylation of KLF5 at Arginine 57 (R57) in a methyltransferase activity-dependent manner in BLBC cells. Depletion or pharmaceutical inhibition (using PJ-68) of PRMT5 decreased the expression of KLF5 and its downstream target genes in vitro and in vivo. PRMT5-induced KLF5R57me2 antagonizes GSK3 beta-mediated KLF5 phosphorylation and subsequently Fbw7-mediated KLF5 ubiquitination and coupled degradation. Functionally, PRMT5 promotes breast cancer stem cell maintenance and proliferation, at least partially, by stabilizing KLF5. PRMT5 and KLF5 protein levels were positively correlated in clinical BLBCs. Taken together, PRMT5 methylates KLF5 to prevent its phosphorylation, ubiquitination, and degradation, and thus promotes breast cancer stem cell maintenance and proliferation. These findings suggest that PRMT5 is a potential therapeutic target for BLBC.
基金：
National Key Research and Development Program of China [2020YFA0112300, 2018YFC2000400]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31771516, 81830087, 81802671, 81872414]; Yunnan Fundamental Research Projects [2019FB112, 202001AW070018]; Project of Innovative Research Team of Yunnan Province [2019HC005]
第一作者机构：[1]Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China[2]KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Kunming, Yunnan, China[3]Kunming College of Life Sciences, University of Chinese Academy Sciences, Kunming, Yunnan, China
共同第一作者：
通讯作者：
通讯机构：[1]Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China[2]KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Kunming, Yunnan, China[3]Kunming College of Life Sciences, University of Chinese Academy Sciences, Kunming, Yunnan, China[11]Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
推荐引用方式(GB/T 7714)：
Wang Xinye,Qiu Ting,Wu Yingying,et al.Arginine methyltransferase PRMT5 methylates and stabilizes KLF5 via decreasing its phosphorylation and ubiquitination to promote basal-like breast cancer[J].CELL DEATH AND DIFFERENTIATION.2021,28(10):2931-2945.doi:10.1038/s41418-021-00793-0.
APA：
Wang, Xinye,Qiu, Ting,Wu, Yingying,Yang, Chuanyu,Li, Yi...&Chen, Ceshi.(2021).Arginine methyltransferase PRMT5 methylates and stabilizes KLF5 via decreasing its phosphorylation and ubiquitination to promote basal-like breast cancer.CELL DEATH AND DIFFERENTIATION,28,(10)
MLA：
Wang, Xinye,et al."Arginine methyltransferase PRMT5 methylates and stabilizes KLF5 via decreasing its phosphorylation and ubiquitination to promote basal-like breast cancer".CELL DEATH AND DIFFERENTIATION 28..10(2021):2931-2945
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