SNORD88B-mediated WRN nucleolar trafficking drives self-renewal in liver cancer initiating cells and hepatocarcinogenesis

• Published in: Nature communications Vol. 15; no. 1; pp. 6730 - 16
• Main Authors: Gu, Yang, Yi, Zhibin, Zhou, Ziheng, Wang, Jianyi, Li, Shan, Zhu, Pingping, Liu, Nian, Xu, Yuwei, He, Lei, Wang, Yanying, Fan, Zusen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 13/105; 13/107; 13/109; 13/31; 13/51; 13/89; 14/32; 14/5; 38/61; 631/337/384/521; 631/67/1504/1610/4029; 631/67/71; Animals; Antisense oligonucleotides; Antitumor activity; Cancer therapies; Carcinogenesis - genetics; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Nucleolus - metabolism; Cell Self Renewal; Gene Expression Regulation, Neoplastic; Hepatocellular carcinoma; Hepatocytes; Hippo Signaling Pathway; Humanities and Social Sciences; Humans; Inactivation; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Medical prognosis; Mice; multidisciplinary; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Nucleoli; Oligonucleotides; Oligonucleotides, Antisense - pharmacology; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; RNA, Small Nucleolar - genetics; RNA, Small Nucleolar - metabolism; Science; Science (multidisciplinary); Signal Transduction; snoRNA; Stem cells; Therapeutic targets; Tumorigenesis; Werner Syndrome Helicase - genetics; Werner Syndrome Helicase - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50987-6

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. The role of small nucleolar RNAs (snoRNAs) in cancer stem cells (CSCs) is not much explored. Here, the authors identify that the snoRNA SNORD88B drives self-renewal of liver CSCs and liver tumorigenesis through promoting the nucleolar shuttle protein WRN retention in the nucleolus and dysregulation of Hippo signaling.