The Conserved LncRNA DIO3OS Restricts Hepatocellular Carcinoma Stemness by Interfering with NONO-Mediated Nuclear Export of ZEB1 mRNA.
The Conserved LncRNA DIO3OS Restricts Hepatocellular Carcinoma Stemness by Interfering with NONO-Mediated Nuclear Export of ZEB1 mRNA.
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DOI：
10.1002/advs.202301983
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发表时间：
2023-08
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影响因子：
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中科院分区：
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Hepatocellular carcinoma (HCC) is an aggressive and fatal disease caused by a subset of cancer stem cells (CSCs). It is estimated that there are approximately 100 000 long noncoding RNAs (lncRNAs) in humans. However, the mechanisms by which lncRNAs affect tumor stemness remain poorly understood. In the present study, it is found that DIO3OS is a conserved lncRNA that is generally downregulated in multiple cancers, including HCC, and its low expression correlates with poor clinical outcomes in HCC. In in vitro cancer cell lines and an in vivo spontaneous HCC mouse model, DIO3OS markedly represses tumor development via its suppressive role in CSCs through downregulation of zinc finger E‐box binding homeobox 1 (ZEB1). Interestingly, DIO3OS represses ZEB1 post‐transcriptionally without affecting its mRNA levels. Subsequent experiments show that DIO3OS interacts with the NONO protein and restricts NONO‐mediated nuclear export of ZEB1 mRNA. Overall, these findings demonstrate that the DIO3OS‐NONO‐ZEB1 axis restricts HCC development and offers a valuable candidate for CSC‐targeted therapeutics for HCC. This study reveals a crucial role of the conserved lncRNA, DIO3OS, in inhibiting the progression of hepatocellular carcinoma (HCC). DIO3OS binds to NONO protein in the nucleus, which reduces the ability of NONO to promote the nuclear export of ZEB1 mRNA. By regulating the cellular distribution of ZEB1 mRNAs, DIO3OS decreases translation of ZEB1 and subsequently suppresses HCC stemness.
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