SNORD88B-mediated WRN nucleolar trafficking drives self-renewal in liver cancer initiating cells and hepatocarcinogenesis
Yang Gu, Zhibin Yi, Ziheng Zhou, Jianyi Wang, Shan Li, Pingping Zhu, Nian Liu, Yuwei Xu, Lei He, Yanying Wang & Zusen Fan
Abstract
Whether small nucleolar RNAs (snoRNAs) are involved in the regulation of liver cancer stem cells (CSCs) self-renewal and serve as therapeutic targets remains largely unclear. Here we show that a functional snoRNA (SNORD88B) is robustly expressed in Hepatocellular carcinoma (HCC) tumors and liver CSCs.SNORD88Bdeficiency abolishes the self-renewal of liver CSCs and hepatocarcinogenesis. Mechanistically,SNORD88Banchors WRN in the nucleolus, promoting XRCC5 interacts withSTK4promoter to suppress its transcription, leading to inactivation of Hippo signaling. Moreover, low expression ofSTK4and high expression of XRCC5 are positively correlated with HCC poor prognosis. Additionally,snord88bknockout suppresses mouse liver tumorigenesis. Notably, co-administration ofSNORD88Bantisense oligonucleotides (ASOs) with MST1 agonist adapalene (ADA) exert synergistic antitumor effects and increase overall murine survival. Our findings delineate thatSNORD88Bdrives self-renewal of liver CSCs and accelerates HCC tumorigenesis via non-canonical mechanism, providing potential targets for liver cancer therapy by eliminating liver CSCs.
附件下载：
SNORD88B-mediated WRN nucleolar trafficking drives self-renewal in liver cancer initiating cells and hepatocarcinogenesis,Nat Commun, 7 Aug 2024
Nature Communications, 7 August, 2024, DOI：https://doi.org/10.1038/s41467-024-50987-6
SNORD88B-mediated WRN nucleolar trafficking drives self-renewal in liver cancer initiating cells and hepatocarcinogenesis
Yang Gu, Zhibin Yi, Ziheng Zhou, Jianyi Wang, Shan Li, Pingping Zhu, Nian Liu, Yuwei Xu, Lei He, Yanying Wang & Zusen Fan
Abstract
Whether small nucleolar RNAs (snoRNAs) are involved in the regulation of liver cancer stem cells (CSCs) self-renewal and serve as therapeutic targets remains largely unclear. Here we show that a functional snoRNA (SNORD88B) is robustly expressed in Hepatocellular carcinoma (HCC) tumors and liver CSCs.SNORD88Bdeficiency abolishes the self-renewal of liver CSCs and hepatocarcinogenesis. Mechanistically,SNORD88Banchors WRN in the nucleolus, promoting XRCC5 interacts withSTK4promoter to suppress its transcription, leading to inactivation of Hippo signaling. Moreover, low expression ofSTK4and high expression of XRCC5 are positively correlated with HCC poor prognosis. Additionally,snord88bknockout suppresses mouse liver tumorigenesis. Notably, co-administration ofSNORD88Bantisense oligonucleotides (ASOs) with MST1 agonist adapalene (ADA) exert synergistic antitumor effects and increase overall murine survival. Our findings delineate thatSNORD88Bdrives self-renewal of liver CSCs and accelerates HCC tumorigenesis via non-canonical mechanism, providing potential targets for liver cancer therapy by eliminating liver CSCs.
文章链接：https://www.nature.com/articles/s41467-024-50987-6