Upregulated YB-1 protein promotes glioblastoma growth through a YB-1/CCT4/mLST8/mTOR pathway
Y-box–binding protein 1 (YB-1) is a multifunctional RNA binding protein involved in virtually every step of RNA metabolism. However, the functions and mechanisms of YB-1 in one of the most aggressive cancers, glioblastoma, are not well understood. In this study, we found that YB-1 protein was marked...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-04-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI146536 |
| _version_ | 1818549508576903168 |
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| author | Jin-Zhu Wang Hong Zhu Pu You Hui Liu Wei-Kang Wang Xiaojuan Fan Yun Yang Keren Xu Yingfeng Zhu Qunyi Li Ping Wu Chao Peng Catherine C.L. Wong Kaicheng Li Yufeng Shi Nu Zhang Xiuxing Wang Rong Zeng Ying Huang Liusong Yang Zefeng Wang Jingyi Hui |
| author_facet | Jin-Zhu Wang Hong Zhu Pu You Hui Liu Wei-Kang Wang Xiaojuan Fan Yun Yang Keren Xu Yingfeng Zhu Qunyi Li Ping Wu Chao Peng Catherine C.L. Wong Kaicheng Li Yufeng Shi Nu Zhang Xiuxing Wang Rong Zeng Ying Huang Liusong Yang Zefeng Wang Jingyi Hui |
| author_sort | Jin-Zhu Wang |
| collection | DOAJ |
| description | Y-box–binding protein 1 (YB-1) is a multifunctional RNA binding protein involved in virtually every step of RNA metabolism. However, the functions and mechanisms of YB-1 in one of the most aggressive cancers, glioblastoma, are not well understood. In this study, we found that YB-1 protein was markedly overexpressed in glioblastoma and acted as a critical activator of both mTORC1 and mTORC2 signaling. Mechanistically, YB-1 bound the 5′UTR of CCT4 mRNA to promote the translation of CCT4, a component of the CCT chaperone complex, that in turn activated the mTOR signaling pathway by promoting mLST8 folding. In addition, YB-1 autoregulated its own translation by binding to its 5′UTR, leading to sustained activation of mTOR signaling. In patients with glioblastoma, high protein expression of YB-1 correlated with increased expression of CCT4 and mLST8 and activated mTOR signaling. Importantly, the administration of RNA decoys specifically targeting YB-1 in a mouse xenograft model resulted in slower tumor growth and better survival. Taken together, these findings uncover a disrupted proteostasis pathway involving a YB-1/CCT4/mLST8/mTOR axis in promoting glioblastoma growth, suggesting that YB-1 is a potential therapeutic target for the treatment of glioblastoma. |
| first_indexed | 2024-12-12T08:34:16Z |
| format | Article |
| id | doaj.art-ba4ef9a35730430dad7215c017706423 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-12-12T08:34:16Z |
| publishDate | 2022-04-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-ba4ef9a35730430dad7215c0177064232022-12-22T00:31:00ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-04-011328Upregulated YB-1 protein promotes glioblastoma growth through a YB-1/CCT4/mLST8/mTOR pathwayJin-Zhu WangHong ZhuPu YouHui LiuWei-Kang WangXiaojuan FanYun YangKeren XuYingfeng ZhuQunyi LiPing WuChao PengCatherine C.L. WongKaicheng LiYufeng ShiNu ZhangXiuxing WangRong ZengYing HuangLiusong YangZefeng WangJingyi HuiY-box–binding protein 1 (YB-1) is a multifunctional RNA binding protein involved in virtually every step of RNA metabolism. However, the functions and mechanisms of YB-1 in one of the most aggressive cancers, glioblastoma, are not well understood. In this study, we found that YB-1 protein was markedly overexpressed in glioblastoma and acted as a critical activator of both mTORC1 and mTORC2 signaling. Mechanistically, YB-1 bound the 5′UTR of CCT4 mRNA to promote the translation of CCT4, a component of the CCT chaperone complex, that in turn activated the mTOR signaling pathway by promoting mLST8 folding. In addition, YB-1 autoregulated its own translation by binding to its 5′UTR, leading to sustained activation of mTOR signaling. In patients with glioblastoma, high protein expression of YB-1 correlated with increased expression of CCT4 and mLST8 and activated mTOR signaling. Importantly, the administration of RNA decoys specifically targeting YB-1 in a mouse xenograft model resulted in slower tumor growth and better survival. Taken together, these findings uncover a disrupted proteostasis pathway involving a YB-1/CCT4/mLST8/mTOR axis in promoting glioblastoma growth, suggesting that YB-1 is a potential therapeutic target for the treatment of glioblastoma.https://doi.org/10.1172/JCI146536Oncology |
| spellingShingle | Jin-Zhu Wang Hong Zhu Pu You Hui Liu Wei-Kang Wang Xiaojuan Fan Yun Yang Keren Xu Yingfeng Zhu Qunyi Li Ping Wu Chao Peng Catherine C.L. Wong Kaicheng Li Yufeng Shi Nu Zhang Xiuxing Wang Rong Zeng Ying Huang Liusong Yang Zefeng Wang Jingyi Hui Upregulated YB-1 protein promotes glioblastoma growth through a YB-1/CCT4/mLST8/mTOR pathway The Journal of Clinical Investigation Oncology |
| title | Upregulated YB-1 protein promotes glioblastoma growth through a YB-1/CCT4/mLST8/mTOR pathway |
| title_full | Upregulated YB-1 protein promotes glioblastoma growth through a YB-1/CCT4/mLST8/mTOR pathway |
| title_fullStr | Upregulated YB-1 protein promotes glioblastoma growth through a YB-1/CCT4/mLST8/mTOR pathway |
| title_full_unstemmed | Upregulated YB-1 protein promotes glioblastoma growth through a YB-1/CCT4/mLST8/mTOR pathway |
| title_short | Upregulated YB-1 protein promotes glioblastoma growth through a YB-1/CCT4/mLST8/mTOR pathway |
| title_sort | upregulated yb 1 protein promotes glioblastoma growth through a yb 1 cct4 mlst8 mtor pathway |
| topic | Oncology |
| url | https://doi.org/10.1172/JCI146536 |
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