PMID- 38049865 OWN - NLM STAT- MEDLINE DCOM- 20231206 LR - 20231207 IS - 1756-9966 (Electronic) IS - 0392-9078 (Print) IS - 0392-9078 (Linking) VI - 42 IP - 1 DP - 2023 Dec 5 TI - SNORA56-mediated pseudouridylation of 28 S rRNA inhibits ferroptosis and promotes colorectal cancer proliferation by enhancing GCLC translation. PG - 331 LID - 10.1186/s13046-023-02906-8 [doi] LID - 331 AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies and is characterized by reprogrammed metabolism. Ferroptosis, a programmed cell death dependent on iron, has emerged as a promising strategy for CRC treatment. Although small nucleolar RNAs are extensively involved in carcinogenesis, it is unclear if they regulate ferroptosis during CRC pathogenesis. METHODS: The dysregulated snoRNAs were identified using published sequencing data of CRC tissues. The expression of the candidate snoRNAs, host gene and target gene were assessed by real-time quantitative PCR (RT-qPCR), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and western blots. The biological function of critical molecules was investigated using in vitro and in vivo strategies including Cell Counting Kit-8 (CCK8), colony formation assay, flow cytometry, Fe(2+)/Fe(3+), GSH/GSSG and the xenograft mice models. The ribosomal activities were determined by polysome profiling and O-propargyl-puromycin (OP-Puro) assay. The proteomics was conducted to clarify the downstream targets and the underlying mechanisms were validated by IHC, Pearson correlation analysis, protein stability and rescue assays. The clinical significance of the snoRNA was explored using the Cox proportional hazard model, receiver operating characteristic (ROC) and survival analysis. RESULTS: Here, we investigated the SNORA56, which was elevated in CRC tissues and plasma, and correlated with CRC prognosis. SNORA56 deficiency in CRC impaired proliferation and triggered ferroptosis, resulting in reduced tumorigenesis. Mechanistically, SNORA56 mediated the pseudouridylation of 28 S rRNA at the U1664 site and promoted the translation of the catalytic subunit of glutamate cysteine ligase (GCLC), an indispensable rate-limiting enzyme in the biosynthesis of glutathione, which can inhibit ferroptosis by suppressing lipid peroxidation. CONCLUSIONS: Therefore, the SNORA56/28S rRNA/GCLC axis stimulates CRC progression by inhibiting the accumulation of cellular peroxides, and it may provide biomarker and therapeutic applications in CRC. CI - (c) 2023. The Author(s). FAU - Xu, Chang AU - Xu C AD - Department of Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China. FAU - Bian, Zhixuan AU - Bian Z AD - Department of Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. AD - College of Health Science and Technology, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China. AD - Shanghai Key Laboratory of Clinical Molecular Diagnostics for Paediatrics, Shanghai, 200127, China. AD - Sanya Women and Children's Hospital Managed by Shanghai Children's Medical Center, Sanya, 572000, China. FAU - Wang, Xinyue AU - Wang X AD - Department of Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China. FAU - Niu, Na AU - Niu N AD - Department of Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China. FAU - Liu, Li AU - Liu L AD - Department of Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. AD - College of Health Science and Technology, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China. AD - Shanghai Key Laboratory of Clinical Molecular Diagnostics for Paediatrics, Shanghai, 200127, China. FAU - Xiao, Yixuan AU - Xiao Y AD - Department of Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. AD - College of Health Science and Technology, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China. AD - Shanghai Key Laboratory of Clinical Molecular Diagnostics for Paediatrics, Shanghai, 200127, China. FAU - Zhu, Jiabei AU - Zhu J AD - Department of Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. AD - College of Health Science and Technology, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China. AD - Shanghai Key Laboratory of Clinical Molecular Diagnostics for Paediatrics, Shanghai, 200127, China. FAU - Huang, Nan AU - Huang N AD - Department of Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China. FAU - Zhang, Yue AU - Zhang Y AD - Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China. FAU - Chen, Yan AU - Chen Y AD - Department of Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China. FAU - Wu, Qi AU - Wu Q AD - Department of Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China. FAU - Sun, Fenyong AU - Sun F AD - Department of Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China. FAU - Zhu, Xiaoli AU - Zhu X AD - Department of Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China. xiaolizhu@tongji.edu.cn. FAU - Pan, Qiuhui AU - Pan Q AD - Department of Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. panqiuhui@scmc.com.cn. AD - College of Health Science and Technology, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China. panqiuhui@scmc.com.cn. AD - Shanghai Key Laboratory of Clinical Molecular Diagnostics for Paediatrics, Shanghai, 200127, China. panqiuhui@scmc.com.cn. AD - Sanya Women and Children's Hospital Managed by Shanghai Children's Medical Center, Sanya, 572000, China. panqiuhui@scmc.com.cn. LA - eng GR - 81930066/the National Natural Science Foundation of China/ GR - 82172357/the National Natural Science Foundation of China/ GR - 82293662/the National Natural Science Foundation of China/ GR - 2019CXJQ03/the Innovation Group Project of Shanghai Municipal Health Commission/ GR - 22JC1402300/Science and Technology Innovation Plan Of Shanghai Science and Technology Commission/ PT - Journal Article DEP - 20231205 PL - England TA - J Exp Clin Cancer Res JT - Journal of experimental & clinical cancer research : CR JID - 8308647 RN - EC 6.3.2.2 (GCLC protein, human) RN - EC 6.3.2.2 (Glutamate-Cysteine Ligase) RN - 0 (RNA, Ribosomal) RN - 0 (RNA, Small Nuclear) SB - IM MH - Animals MH - Humans MH - Mice MH - Carcinogenesis MH - Cell Line, Tumor MH - Cell Proliferation MH - *Colorectal Neoplasms/genetics MH - *Ferroptosis/genetics MH - *Glutamate-Cysteine Ligase MH - In Situ Hybridization, Fluorescence MH - RNA, Ribosomal MH - *RNA, Small Nuclear/genetics PMC - PMC10696674 OTO - NOTNLM OT - Biomarker OT - Colorectal cancer OT - Ferroptosis OT - GCLC OT - Proliferation OT - Pseudouridylation OT - SNORA56 OT - Therapy COIS- The authors declare that they have no competing interests. EDAT- 2023/12/05 00:42 MHDA- 2023/12/06 06:42 PMCR- 2023/12/05 CRDT- 2023/12/04 23:54 PHST- 2023/09/09 00:00 [received] PHST- 2023/11/16 00:00 [accepted] PHST- 2023/12/06 06:42 [medline] PHST- 2023/12/05 00:42 [pubmed] PHST- 2023/12/04 23:54 [entrez] PHST- 2023/12/05 00:00 [pmc-release] AID - 10.1186/s13046-023-02906-8 [pii] AID - 2906 [pii] AID - 10.1186/s13046-023-02906-8 [doi] PST - epublish SO - J Exp Clin Cancer Res. 2023 Dec 5;42(1):331. doi: 10.1186/s13046-023-02906-8.