Targeting HSPA1A in ARID2-deficient lung adenocarcinoma  

作　　者：Xue Wang Yuetong Wang Zhaoyuan Fang Hua Wang Jian Zhang Longfu Zhang Hsinyi Huang Zhonglin Jiang Yujuan Jin Xiangkun Han Shenda Hou Bin Zhou Feilong Meng Luonan Chen Kwok-Kin Wong Jinfeng Liu Zhiqi Zhang Xin Zhang Haiquan Chen Yihua Sun Liang Hu Hongbin Ji 

机构地区：[1]State Key Laboratory of Cell Biology,Shanghai Institute of Biochemistry and Cell Biology,Center for Excellence in Molecular Cell Science,Chinese Academy of Sciences,Shanghai 200031,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]Department of Pulmonary Medicine,Zhong Shan Hospital,Fudan University,Shanghai 200032,China [4]Division of Hematology and Medical Oncology,Laura and Isaac Perlmutter Cancer Center,New York University Langone Medical Center,New York,NY 10016,USA [5]College of Life Sciences,Qufu Normal University,Qufu 273165,China [6]Shanghai University of Medicine and Health Sciences,Shanghai Sixth People's Hospital East Campus,Shanghai 201306,China [7]Department of General Surgery,Shanghai Jiao Tong University Affiliated Sixth People's Hospital,Shanghai 200233,China [8]Department of Thoracic Surgery,Fudan University Shanghai Cancer Center,Shanghai 200032,China [9]School of Life Science and Technology,Shanghai Tech University,Shanghai 200120,China [10]School of Life Science,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China

出　　处：《National Science Review》2021年第10期84-95,共12页国家科学评论（英文版）

基　　金：supported by the National Basic Research Program of China(2017YFA0505501 to H.J.);the National Basic Research Program of China(2020YFA0803300 to H.J.);the National Natural Science Foundation of China(grants 81902326 to X.W.,82030083 to H.J.,81872312 to H.J.,82011540007 to H.J.,31621003 to H.J.,91731314 to H.J.,81871875 to L.H.,81402371 to Y.J.,81802279 to H.H.,81602459 to Z.F.);the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB19020201 to H.J.);the Basic Frontier Scientific Research Program of Chinese Academy of Sciences(ZDBS-LY-SM006 to H.J.);the International Cooperation Project of Chinese Academy of Sciences(153D31KYSB20190035 to H.J.);the Youth Innovation Promotion Association CAS(Y919S31371 to X.W.)。

摘　　要：Somatic mutations of the chromatin remodeling gene ARID2 are observed in~7%of human lung adenocarcinomas(LUADs).However,the role of ARID2 in the pathogenesis of LUADs remains largely unknown.Here we find that ARID2 expression is decreased during the malignant progression of both human and mice LUADs.Using two Kras^(G12D)-based genetically engineered murine models,we demonstrate that ARID2 knockout significantly promotes lung cancer malignant progression and shortens overall survival.Consistently,ARID2 knockdown significantly promotes cell proliferation in human and mice lung cancer cells.Through integrative analyses of Ch IP-Seq and RNA-Seq data,we find that Hspa1 a is up-regulated by Arid2 loss.Knockdown of Hspa1 a specifically inhibits malignant progression of Arid2-deficient but not Arid2-wt lung cancers in both cell lines as well as animal models.Treatment with an HSPA1 A inhibitor could significantly inhibit the malignant progression of lung cancer with ARID2 deficiency.Together,our findings establish ARID2 as an important tumor suppressor in LUADs with novel mechanistic insights,and further identify HSPA1 A as a potential therapeutic target in ARID2-deficient LUADs.

关 键 词：lung adenocarcinoma tumor suppressor ARID2 HSPA1A 

分 类 号：R734.2[医药卫生—肿瘤]