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Non-coding small nucleolar RNA SNORD17 promotes the progression of hepatocellular carcinoma through a positive feedback loop upon p53 inactivation

Abstract

Recent evidence suggests that small nucleolar RNAs (snoRNAs) are involved in the progression of various cancers, but their precise roles in hepatocellular carcinoma (HCC) remain largely unclear. Here, we report that SNORD17 promotes the progression of HCC through a positive feedback loop with p53. HCC-related microarray datasets from the Gene Expression Omnibus (GEO) database and clinical HCC samples were used to identify clinically relevant snoRNAs 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. SNORD17 promoted the growth and tumorigenicity of HCC cells in vitro and in vivo by inhibiting p53-mediated cell cycle arrest and apoptosis. Mechanistically, SNORD17 anchored nucleophosmin 1 (NPM1) and MYB binding protein 1a (MYBBP1A) in the nucleolus by binding them simultaneously. Loss of SNORD17 promoted the translocation of NPM1 and MYBBP1A 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. In summary, this study suggests that SNORD17 drives cancer progression by constitutively inhibiting p53 signaling in HCC and may represent a potential therapeutic target for HCC.

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Fig. 1: Identification of SNORD17 as a clinically relevant snoRNA in HCC.
Fig. 2: SNORD17 promotes the proliferation, cell cycle progression, and apoptosis resistance of HCC cells in vitro and in vivo.
Fig. 3: SNORD17 affects p53-dependent HCC cell growth.
Fig. 4: SNORD17 promotes MDM2-mediated p53 ubiquitination via NPM1.
Fig. 5: SNORD17 promotes p300-mediated p53 acetylation via MYBBP1A.
Fig. 6: SNORD17 anchors NPM1 and MYBBP1A in the nucleolus by simultaneous binding with them.
Fig. 7: p53 represses SNORD17 expression via a p300-dependent manner.
Fig. 8: Clinical significance of SNORD17 in HCC patients with wild-type p53 and the therapeutical application of SNORD17.

Data availability

All datasets on which the conclusions of the paper rely are attached in the main paper or additional supporting files.

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Acknowledgements

We would like to thank Prof. Chaoyang Li (Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, 510095, China.) for his kind suggestions on manuscript composition. We would like to thank Prof. Jiahuai Han (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Department of Biology, School of Life Sciences, Xiamen University, Xiamen, 361005, China.) for donating plasmids. We thank Shanghai Bioprofile Technology Company Ltd for technological assistance in mass spectrum assay. This study was supported by the National Natural Science Foundation of China (Nos. 82172971, 31671348, 81874065, 81874189), the National Key Research and Development Program of China (2018YFA0208904), Chen Xiao-ping Foundation for the Development of Science and Technology of Hubei Province under Grant (CXPJJH12000001-2020317).

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BXZ, XPC, LC, PKD, and JNL designed the experiments. JNL, GXL, ZH, and JYL performed most of the experiments and acquisition of data with assistance from ZH, JYW, WQX, ZYC, GZC, ZYD, HFL, and YW. JNL, ZH, PKD, and GXL wrote the paper and critically reviewed the paper. All authors read and approved the final version of the paper.

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Correspondence to Liang Chu, Xiaoping Chen or Bixiang Zhang.

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Animal experimental procedures were approved by the Committee on the Ethics of Animal Experiments of Tongji Hospital (TJH-201809003). Use of tissue from HCC patients was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (Wuhan, China) (TJ-IRB20210924).

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Liang, J., Li, G., Liao, J. et al. Non-coding small nucleolar RNA SNORD17 promotes the progression of hepatocellular carcinoma through a positive feedback loop upon p53 inactivation. Cell Death Differ 29, 988–1003 (2022). https://doi.org/10.1038/s41418-022-00929-w

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