Non-coding Small Nucleolar RNA SNORD17 Promotes The Progression Of Hepatocellular Carcinoma Through A Positive Feedback Loop Upon P53 Inactivation

Background and aims:Hepatocellular carcinoma(HCC)is one of the most common tumors with the highest mortality worldwide,with a global incidence of about 840 thousand per year,ranking 7th in the incidence of various malignant tumors and 4th in the fatality rate.Although HCC treatment has dramatically improved over the last decades,the incidence and cancer-specific mortality of HCC continues to increase in many countries,mainly due to the limited understanding of the underlying molecular pathogenesis.Small nucleolar RNA(Sno RNAs)are conserved non-coding RNAs with a length of 60 to 300 nucleotides.They are wellknown for their role as small nucleolar ribonucleoproteins(sno RNPs)guides in posttranscriptional modification and maturation of ribosomal RNAs(r RNAs).In recent years,it has been reported that sno RNAs are inextricably linked to cancer progression.However,the role and molecular mechanism of small nucleolar RNA in the development and progression of hepatocellular carcinoma remains unclear.Approach and Results:HCC-related microarray datasets from the Gene Expression Omnibus(GEO)database and clinical HCC samples were used to identify clinically relevant sno RNAs in HCC.SNORD17 was found upregulated in HCC tissues compared with normal liver tissues,and the higher expression of SNORD17 predicted poor outcomes in patients with HCC,especially in those with wild-type p53.Univariate and multivariate cox regression analysis showed that SNORD17 was an independent risk factor for HCC death.The functional role of SNORD17 in HCC was investigated using a series of in vitro and in vivo experiments.SNORD17 promoted the growth and tumorigenicity of HCC cells in vitro and in vivo by inhibiting p53-mediated cell cycle arrest and apoptosis.Immunoprecipitation,ubiquitination,subcellular fractionation and chromatin immunoprecipitation assays were used to elucidate the mechanism of mutual regulation between SNORD17 and p53.Mechanistically,SNORD17 anchored nucleophosmin 1(NPM1)and MYB binding protein1a(MYBBP1A)in the nucleolus by binding them simultaneously.Loss of SNORD17 promoted the translocation of NPM1 and MYBBP1 A into the nucleoplasm,leading to NPM1/MDM2-mediated stability and MYBBP1A/p300-mediated activation of p53.Interestingly,p300-mediated acetylation of p53 inhibited SNORD17 expression by binding to the promoter of SNORD17 in turn,forming a positive feedback loop between SNORD17 and p53.Administration of SNORD17 antisense oligonucleotides(ASOs)significantly suppressed the growth of xenograft tumors in mice.ConclusionsSNORD17 drives cancer progression by constitutively inhibiting p53 signalling in HCC and may represent a potential therapeutic target for HCC.