Upregulated YB-1 protein promotes glioblastoma growth through a YB-1/CCT4/mLST8/mTOR pathway.

Abstract

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.

• Authors: 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 Cl Wong, Kaicheng Li, Yufeng Shi, Nu Zhang, Xiuxing Wang, Rong Zeng, Ying Huang, Liusong Yang, Zefeng Wang, Jingyi Hui
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 132 Issue 8 (04 15 2022) ISSN: 1558-8238 [Electronic] United States
• PMID: 35239512 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5' Untranslated Regions
• CCT4 protein, human
• MLST8 protein, human
• Transcription Factors
• Y-Box-Binding Protein 1
• YBX1 protein, human
• mTOR Associated Protein, LST8 Homolog
• MTOR protein, human
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• Chaperonin Containing TCP-1

Topics

• 5' Untranslated Regions
• Animals
• Cell Line, Tumor
• Chaperonin Containing TCP-1
• Glioblastoma (genetics)
• Humans
• Mechanistic Target of Rapamycin Complex 1 (genetics, metabolism)
• Mice
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Transcription Factors (genetics)
• Y-Box-Binding Protein 1 (genetics, metabolism)
• mTOR Associated Protein, LST8 Homolog (genetics, metabolism)