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Cell death and differentiation
05, 2022;29 (5): 988-1003.

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

Junnan Liang, Ganxun Li, Jingyu Liao, Zhao Huang, Jingyuan Wen, Yu Wang, Zeyu Chen, Guangzhen Cai, Weiqi Xu, Zeyang Ding, Huifang Liang, Pran K Datta, Liang Chu, Xiaoping Chen, Bixiang Zhang
Author Information
  1. Junnan Liang: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  2. Ganxun Li: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  3. Jingyu Liao: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. ORCID
  4. Zhao Huang: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  5. Jingyuan Wen: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  6. Yu Wang: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  7. Zeyu Chen: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  8. Guangzhen Cai: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  9. Weiqi Xu: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  10. Zeyang Ding: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  11. Huifang Liang: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. ORCID
  12. Pran K Datta: Division of Hematology and Oncology, Department of Medicine, UAB Comprehensive Cancer Center, Birmingham, AL, USA.
  13. Liang Chu: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Liangchu@tjh.tjmu.edu.cn. ORCID
  14. Xiaoping Chen: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. chenxpchenxp@163.com. ORCID
  15. Bixiang Zhang: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. bixiangzhang@163.com. ORCID
PMID: 35034103 DOI: 10.1038/s41418-022-00929-w

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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MeSH Term

Animals
Carcinoma, Hepatocellular
Cell Line, Tumor
Cell Proliferation
DNA-Binding Proteins
Feedback
Gene Expression Regulation, Neoplastic
Humans
Liver Neoplasms
Mice
Nucleophosmin
RNA, Small Nucleolar
RNA-Binding Proteins
Transcription Factors
Tumor Suppressor Protein p53

Chemicals

DNA-Binding Proteins
MYBBP1A protein, human
NPM1 protein, human
RNA, Small Nucleolar
RNA-Binding Proteins
Transcription Factors
Tumor Suppressor Protein p53
Nucleophosmin
Journal Article Research Support, Non-U.S. Gov't

Word Cloud

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