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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.
Highlights
Recent large-scale surveys of proteins identified more than 1500 RNA binding proteins that bind to single- or double-stranded RNAs [1–4]
We discovered that Y-box–binding protein 1 (YB-1) can function as a critical activator of mammalian target of rapamycin (mTOR) signaling through mediating a self-activated pathway that impairs the protein homeostasis program in glioblastoma (Figure 9N)
Our results showed that the level of YB-1 protein but not its mRNA is markedly elevated and predicts a poor prognosis
Summary
Recent large-scale surveys of proteins identified more than 1500 RNA binding proteins that bind to single- or double-stranded RNAs [1–4]. Dysregulation of RNA binding proteins has been linked to various human diseases, especially in cancers where a number of RNA binding proteins function as master regulators during cancer development and progression [6, 7]. Our current understanding of the molecular roles of RNA binding proteins in cancer remains very limited. The majority of patients with glioblastoma receive surgical resection followed by radiation and chemotherapy [10, 11]. Despite these therapeutic interventions, glioblastoma is associated with a poor prognosis, with a 5-year survival rate of 5.1% and a median survival of 15 to 23 months [12, 13]. Some new investigational treatments, including targeted, radio-, chemo-, and immunotherapies, only yielded limited improvement of patient outcome [14]. A better understanding of the key molecules and pathways that trigger glioblastoma is warranted, which will facilitate the identification of novel targets for early diagnosis and effective treatment of glioblastoma
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