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 () and Zusen Fan ()
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Yang Gu: Chinese Academy of Sciences
Zhibin Yi: Chinese Academy of Sciences
Ziheng Zhou: Chinese Academy of Sciences
Jianyi Wang: Chinese Academy of Sciences
Shan Li: University of Chinese Academy of Sciences
Pingping Zhu: Zhengzhou University
Nian Liu: Chinese Academy of Sciences
Yuwei Xu: Chinese Academy of Sciences
Lei He: PLA General Hospital
Yanying Wang: Chinese Academy of Sciences
Zusen Fan: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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. SNORD88B deficiency abolishes the self-renewal of liver CSCs and hepatocarcinogenesis. Mechanistically, SNORD88B anchors WRN in the nucleolus, promoting XRCC5 interacts with STK4 promoter to suppress its transcription, leading to inactivation of Hippo signaling. Moreover, low expression of STK4 and high expression of XRCC5 are positively correlated with HCC poor prognosis. Additionally, snord88b knockout suppresses mouse liver tumorigenesis. Notably, co-administration of SNORD88B antisense oligonucleotides (ASOs) with MST1 agonist adapalene (ADA) exert synergistic antitumor effects and increase overall murine survival. Our findings delineate that SNORD88B drives self-renewal of liver CSCs and accelerates HCC tumorigenesis via non-canonical mechanism, providing potential targets for liver cancer therapy by eliminating liver CSCs.

Date: 2024
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DOI: 10.1038/s41467-024-50987-6

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