Heat shock protein 90 promotes RNA helicase DDX5 accumulation and exacerbates hepatocellular carcinoma by inhibiting autophagy
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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China Anti-Cancer Association
2021-08-01
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| Series: | Cancer Biology & Medicine |
| Subjects: | |
| Online Access: | http://www.cancerbiomed.org/index.php/cocr/article/view/1830 |
| _version_ | 1818357017526403072 |
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| author | Ting Zhang Xinrui Yang Wanping Xu Jing Wang Dawei Wu Zhixian Hong Shengxian Yuan Zhen Zeng Xiaodong Jia Shanshan Lu Rifaat Safadi Sen Han Zhihong Yang Leonard M. Neckers Suthat Liangpunsakul Weiping Zhou Yinying Lu |
| author_facet | Ting Zhang Xinrui Yang Wanping Xu Jing Wang Dawei Wu Zhixian Hong Shengxian Yuan Zhen Zeng Xiaodong Jia Shanshan Lu Rifaat Safadi Sen Han Zhihong Yang Leonard M. Neckers Suthat Liangpunsakul Weiping Zhou Yinying Lu |
| author_sort | Ting Zhang |
| collection | DOAJ |
| description | 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 mRNA 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 the β-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. |
| first_indexed | 2024-12-13T20:06:25Z |
| format | Article |
| id | doaj.art-984ca1114e1647d6ba9af5a5f0dd2cc7 |
| institution | Directory Open Access Journal |
| issn | 2095-3941 |
| language | English |
| last_indexed | 2024-12-13T20:06:25Z |
| publishDate | 2021-08-01 |
| publisher | China Anti-Cancer Association |
| record_format | Article |
| series | Cancer Biology & Medicine |
| spelling | doaj.art-984ca1114e1647d6ba9af5a5f0dd2cc72022-12-21T23:33:00ZengChina Anti-Cancer AssociationCancer Biology & Medicine2095-39412021-08-0118369370410.20892/j.issn.2095-3941.2020.0262Heat shock protein 90 promotes RNA helicase DDX5 accumulation and exacerbates hepatocellular carcinoma by inhibiting autophagyTing Zhang0Xinrui Yang1Wanping Xu2Jing Wang3Dawei Wu4Zhixian Hong5Shengxian Yuan6Zhen Zeng7Xiaodong Jia8Shanshan Lu9Rifaat Safadi10Sen Han11Zhihong Yang12Leonard M. Neckers13Suthat Liangpunsakul14Weiping Zhou15Yinying Lu16Department of the Fifth Medical Center, General Hospital of PLA, Beijing 100039, ChinaDepartment of the Fifth Medical Center, General Hospital of PLA, Beijing 100039, ChinaUrologic Oncologic Branch, Center for Cancer Research, National Cancer Institute, Bethesda 20814, USAState Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100039, ChinaDepartment of the Fifth Medical Center, General Hospital of PLA, Beijing 100039, ChinaDepartment of the Fifth Medical Center, General Hospital of PLA, Beijing 100039, ChinaThe Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, ChinaDepartment of the Fifth Medical Center, General Hospital of PLA, Beijing 100039, ChinaDepartment of the Fifth Medical Center, General Hospital of PLA, Beijing 100039, ChinaDepartment of the Fifth Medical Center, General Hospital of PLA, Beijing 100039, ChinaHadassah Medical Organization, Hadassah Hebrew University Medical Center, Jerusalem 9112001, IsraelDivision of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis 46202, USADivision of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis 46202, USAState Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100039, ChinaDivision of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis 46202, USAThe Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, ChinaDepartment of the Fifth Medical Center, General Hospital of PLA, Beijing 100039, ChinaObjective: 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 mRNA 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 the β-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.http://www.cancerbiomed.org/index.php/cocr/article/view/1830hepatocellular carcinomaheat shock protein 90rna helicase ddx5autophagyβ-catenin pathway |
| spellingShingle | Ting Zhang Xinrui Yang Wanping Xu Jing Wang Dawei Wu Zhixian Hong Shengxian Yuan Zhen Zeng Xiaodong Jia Shanshan Lu Rifaat Safadi Sen Han Zhihong Yang Leonard M. Neckers Suthat Liangpunsakul Weiping Zhou Yinying Lu Heat shock protein 90 promotes RNA helicase DDX5 accumulation and exacerbates hepatocellular carcinoma by inhibiting autophagy Cancer Biology & Medicine hepatocellular carcinoma heat shock protein 90 rna helicase ddx5 autophagy β-catenin pathway |
| title | Heat shock protein 90 promotes RNA helicase DDX5 accumulation and exacerbates hepatocellular carcinoma by inhibiting autophagy |
| title_full | Heat shock protein 90 promotes RNA helicase DDX5 accumulation and exacerbates hepatocellular carcinoma by inhibiting autophagy |
| title_fullStr | Heat shock protein 90 promotes RNA helicase DDX5 accumulation and exacerbates hepatocellular carcinoma by inhibiting autophagy |
| title_full_unstemmed | Heat shock protein 90 promotes RNA helicase DDX5 accumulation and exacerbates hepatocellular carcinoma by inhibiting autophagy |
| title_short | Heat shock protein 90 promotes RNA helicase DDX5 accumulation and exacerbates hepatocellular carcinoma by inhibiting autophagy |
| title_sort | heat shock protein 90 promotes rna helicase ddx5 accumulation and exacerbates hepatocellular carcinoma by inhibiting autophagy |
| topic | hepatocellular carcinoma heat shock protein 90 rna helicase ddx5 autophagy β-catenin pathway |
| url | http://www.cancerbiomed.org/index.php/cocr/article/view/1830 |
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