Heat shock protein 90 promotes RNA helicase DDX5 accumulation and exacerbates hepatocellular carcinoma by inhibiting autophagy

查看全文 作　　者：Ting [1,2]Zhang;Xinrui [1]Yang;Wanping [3]Xu;Jing [4]Wang;Dawei [1]Wu;Zhixian [1]Hong;Shengxian [5]Yuan;Zhen [1]Zeng;Xiaodong [1]Jia;Shanshan [1]Lu;Rifaat [6]Safadi;Sen [2]Han;Zhihong [2]Yang;Leonard [4]M.Neckers;Suthat [2,7]Liangpunsakul;Weiping [5]Zhou;Yinying [1,8]Lu

机构地区：[1]Department of the Fifth Medical Center,General Hospital of PLA,Beijing 100039,China;[2]Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University School of Medicine,Indianapolis 46202,USA;[3]Urologic Oncologic Branch,Center for Cancer Research,National Cancer Institute,Bethesda 20814,USA;[4]State Key Laboratory of Toxicology and Medical Countermeasures,Beijing Institute of Pharmacology and Toxicology,Beijing 100039,China;[5]The Third Department of Hepatic Surgery,Eastern Hepatobiliary Surgery Hospital,Shanghai 200438,China;[6]Hadassah Medical Organization,Hadassah Hebrew University Medical Center,Jerusalem 9112001,Israel;[7]Department of Biochemistry and Molecular Biology,Indiana University School of Medicine,Indianapolis 46202,USA;[8]Center for Synthetic and Systems Biology(CSSB),Tsinghua University,Beijing 100085,China

出　　处：《Cancer Biology & Medicine》索引2021年第18卷第3期,共12页

基　　金：funding support from the National Natural Science Foundation of China(Grant Nos.81672467,81702773,81702389,and 81672368);the Major National R&D Project(Grant Nos.2018ZX10723204,2018ZX10302205,and 2018ZX09J18107);the Natural Science Foundation of Beijing(Grant No.7172207)。 摘　　要：Objective:Hepatocellular carcinoma(HCC),the main type of liver cancer,has a high morbidity and mortality,and a poor prognosis.RNA helicase DDX5,which acts as a transcriptional co-regulator,is overexpressed in most malignant tumors and promotes cancer cell growth.Heat shock protein 90(HSP90)is an important molecular chaperone in the conformational maturation and stabilization of numerous proteins involved in cell growth or survival.Methods:DDX5 m RNA and protein expression in surgically resected HCC tissues from 24 Asian patients were detected by quantitative real-time PCR and Western blot,respectively.The interaction of DDX5-HSP90 was determined by molecular docking,immunoprecipitation,and laser scanning confocal microscopy.The autophagy signal was detected by Western blot.The cell functions and signaling pathways of DDX5 were determined in 2 HCC cell lines.Two different murine HCC xenograft models were used to determine the function of DDX5 and the therapeutic effect of an HSP90 inhibitor.Results:HSP90 interacted directly with DDX5 and inhibited DDX5 protein degradation in the AMPK/ULK1-regulated autophagy pathway.The subsequent accumulation of DDX5 protein induced the malignant phenotype of HCC by activating theβ-catenin signaling pathway.The silencing of DDX5 or treatment with HSP90 inhibitor both blocked in vivo tumor growth in a murine HCC xenograft model.High levels of HSP90 and DDX5 protein were associated with poor prognoses.Conclusions:HSP90 interacted with DDX5 protein and subsequently protected DDX5 protein from AMPK/ULK1-regulated autophagic degradation.DDX5 and HSP90 are therefore potential therapeutic targets for HCC. 关键词：Hepatocellular carcinoma heat shock protein 90 RNA helicase DDX5 AUTOPHAGY β-catenin pathway

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Heat shock protein 90 promotes RNA helicase DDX5 accumulation and exacerbates hepatocellular carcinoma by inhibiting autophagy

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