Inhibiting the Otub1/phosphorylated STAT3 axis for the treatment of non-small cell lung cancer  

作　　者：Zi-yang Liu Ya-wen Zhang Hai-xia Zhuang Yu-jie Qu Qiu-yun Jiang Ping-fei Li Yuan-ming He Yina Ren Xin-liana Mao 

机构地区：[1]The Key Laboratory of Advanced Interdisciplinary Studies,The First Affiliated Hospital of Guangzhou Medical University&Guangdong Provincial Key Laboratory of Protein Modification and Degradation,School of Basic Medical Sciences,Guangzhou Medical University,Guangzhou 511436,China [2]Department of Pharmacology,College of Pharmaceutical Sciences,Soochow University,Suzhou 215123,China [3]Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy,Xuzhou Medical University,209 TongshanRoad,Xuzhou221004,China

出　　处：《Acta Pharmacologica Sinica》2025年第1期184-195,共12页中国药理学报(英文版)

基　　金：This work was partly supported by Special Projects in Key Areas for Guangdong Provincial Colleges and Universities(#2021ZDZX2009 to XLM);the National Natural Science Foundation of China(#32100577 to YR);the Guangzhou Municipal Science and Technology Project(#202002030059 to XLM);by Guangzhou Medical University Discipline Construction Funds(Basic Medicine)(#JCXKJS2022A05 to XLM).

摘　　要：The transcription factor STAT3 is a promising target for the treatment of non-small cell lung cancer(NSCLC).STAT3 activity is mainly dependent on phosphorylation at tyrosine 705(pSTAT3-Y705),but the modulation on pSTAT3-Y705 is elusive.By screening a library of deubiquitinases(Dubs),we found that the Otub1 increases STAT3 transcriptional activity.As a Dub,Otub1 binds to pSTAT3-Y705 and specifically abolishes its K48-linked ubiquitination,therefore preventing its degradation and promoting NSCLC cell survival.The Otub1/pSTAT3-Y705 axis could be a potential target for the treatment of NSCLC.To explore this concept,we screen libraries of FDAapproved drugs and natural products based on STAT3-recognition element-driven luciferase assay,from which crizotinib is found to block pSTAT3-Y705 deubiquitination and promotes its degradation.Different from its known action to induce ALK positive NSCLC cell apoptosis,crizotinib suppresses ALK-intact NSCLC cell proliferation and colony formation but not apoptosis.Furthermore,crizotinib also suppresses NSCLC xenograft growth in mice.Taken together,these findings identify Otub1 as the first deubiquitinase of pSTAT3-Y705 and provide that the Otub1/pSTAT3-Y705 axis is a promising target for the treatment of NSCLC.

关 键 词：Otub1 STAT3 non-small cell lung cancer CRIZOTINIB 

分 类 号：R73[医药卫生—肿瘤]