SNORA23 inhibits HCC tumorigenesis by impairing the 2'-O-ribose methylation level of 28S rRNA
Zhiyong Liu, Yanan Pang, Yin Jia, Qin Qin, Rui Wang, Wei Li, Jing Jie, Haidong Liu, Shanrong Liu
Abstract
Objective: The dysregulation of ribosome biogenesis is associated with the progression of numerous tumors, includinghepatocellular carcinoma (HCC). Small nucleolar RNAs (snoRNAs) regulate ribosome biogenesis by guiding the modification ofribosomal RNAs (rRNAs). However, the underlying mechanism of this process in HCC remains elusive. Methods: RNA immunoprecipitation and sequencing were used to analyze RNAs targeted by ribosome proteins. The biologicalfunctions of SNORA23 were examined in HCC cells and a xenograft mouse model. To elucidate the underlying mechanisms, the2′-O-ribose methylation level of rRNAs was evaluated by qPCR, and the key proteins in the PI3K/Akt/mTOR pathway were detectedusing Western blot. Results: Twelve snoRNAs were found to co-exist in 4 cancer cell lines using RPS6 pull-down assays. SNORA23 was downregulatedin HCC and correlated with the poor prognoses of HCC patients. SNORA23 inhibited the proliferation, migration, and invasionof HCC cells both in vitro and in vivo. We also found that SNORA23 regulated ribosome biogenesis by impairing 2′-O-ribosemethylation of cytidine4506 of 28S rRNA. Furthermore, SNORA23, which is regulated by the PI3K/Akt/mTOR signaling pathway,significantly inhibited the phosphorylation of 4E binding protein 1. SNORA23 and rapamycin blocked the PI3K/AKT/mTORsignaling pathway and impaired HCC growth in vivo. Conclusions: SNORA23 exhibited antitumor effects in HCC and together with rapamycin, provided a promising therapeuticstrategy for HCC treatment.