The repression of oncoprotein SET by the tumor suppressor p53 reveals a p53-SET-PP2A feedback loop for cancer therapy  

作　　者：Han Yao Wenbin Xu Yajing Liu Zhijie Cao Jia Wen Mi Zhang Zhen Wu Xiaojun Yan Zishan Jiao Zijing Zhang Jianyuan Chen Meng Zhang Wei-Guo Zhu Donglai Wang 

机构地区：[1]State Key Laboratory of Medical Molecular Biology&Department of Medical Genetics,Institute of Basic Medical Sciences&School of Basic Medicine,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100005,China [2]Department of Anatomy,Histology and Embryology,School of Basic Medicine,China Medical University,Shenyang 110122,China [3]Department of Biochemistry and Molecular Biology,Shenzhen University School of Medicine,Shenzhen 518060,China

出　　处：《Science China(Life Sciences)》2023年第1期81-93,共13页中国科学（生命科学英文版）

基　　金：supported by Beijing Municipal Natural Science Foundation(7192126);the National Natural Science Foundation of China(81872311,82073132,82122054,and 81720108027);the National Key R&D Program of China(2019YFC1005200,and 2019YFC1005201);CAMS Innovation Fund for Medical Sciences(2021-I2M-1-016)。

摘　　要：The oncoprotein SET is frequently overexpressed in many types of tumors and contributes to malignant initiation and progression through multiple mechanisms,including the hijacking of the tumor suppressors p53 and PP2A.Targeting aberrant SET represents a promising strategy for cancer intervention.However,the mechanism by which endogenous SET is regulated in cancer cells remains largely unknown.Here,we identified the tumor suppressor p53 as a key regulator that transcriptionally repressed the expression of SET in both normal and cancer cells.In addition,p53 stimulated PP2A phosphatase activity via p53-mediated transcriptional repression of SET,whereby SET-mediated inhibition of PP2A was alleviated.Moreover,targeting the interaction between SET and PP2A catalytic subunit(PP2Ac)with FTY720 enhanced stress-induced p53 activation via PP2A-mediated dephosphorylation of p53 on threonine 55(Thr55).Therefore,our findings uncovered a previously unknown p53-SETPP2A regulatory feedback loop.To functionally potentiate this feedback loop,we designed a combined therapeutic strategy by simultaneously administrating a p53 activator and SET antagonist in cancer cells and observed a dramatic synergistic effect on tumor suppression.Our study reveals mechanistic insight into the regulation of the oncoprotein SET and raises a potential strategy for cancer therapy by stimulating the p53-SET-PP2A feedback loop.

关 键 词：P53 SET PP2A FTY720 feedback loop tumor suppression 

分 类 号：R730.5[医药卫生—肿瘤]