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N4-acetylcytidine modification of lncRNA CTC-490G23.2 promotes cancer metastasis through interacting with PTBP1 to increase CD44 alternative splicing.
- Source :
-
Oncogene [Oncogene] 2023 Mar; Vol. 42 (14), pp. 1101-1116. Date of Electronic Publication: 2023 Feb 16. - Publication Year :
- 2023
-
Abstract
- Although N4-acetylcytidine (ac4C) modification affects the stability and translation of mRNA, it is unknown whether it exists in noncoding RNAs, and its biological function is unclear. Here, nucleotide-resolution method for profiling CTC-490G23.2 ac4C sites and gain- and loss-of-function experiments revealed that N-acetyltransferase 10 (NAT10) is responsible for ac4C modification of long noncoding RNAs (lncRNAs). NAT10-mediated ac4C modification leads to the stabilization and overexpression of lncRNA CTC-490G23.2 in primary esophageal squamous cell carcinoma (ESCC) and its further upregulation in metastatic tissues. CTC-490G23.2 significantly promotes cancer invasion and metastasis in vitro and in vivo. Mechanistically, CTC-490G23.2 acts as a scaffold to increase the binding of CD44 pre-mRNA to polypyrimidine tract-binding protein 1 (PTBP1), resulting in a oncogenic splicing switch from the standard isoform CD44s to the variant isoform CD44v(8-10). CD44v(8-10), but not CD44s, binds to and increases the protein stability of vimentin. Expression levels of CTC-490G23.2 and CD44v(8-10) can predict poor prognosis in cancer patients. Furthermore, the antisense oligonucleotide (ASO)/SV40-LAH4-L1 peptide self-assembled nanocomplexes targeting CTC490G23.2 exerts a significantly suppressive effect on cancer metastasis. The outcome of this study will provide new mechanistic insight into the ac4C modification of lncRNAs and useful clues for the development of novel systemic therapies and prognostic biomarkers.<br /> (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Humans
Alternative Splicing
Protein Isoforms genetics
Gene Expression Regulation, Neoplastic
Hyaluronan Receptors genetics
Hyaluronan Receptors metabolism
Heterogeneous-Nuclear Ribonucleoproteins genetics
Heterogeneous-Nuclear Ribonucleoproteins metabolism
Polypyrimidine Tract-Binding Protein genetics
Polypyrimidine Tract-Binding Protein metabolism
RNA, Long Noncoding genetics
RNA, Long Noncoding metabolism
Esophageal Neoplasms pathology
Esophageal Squamous Cell Carcinoma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 42
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 36792757
- Full Text :
- https://doi.org/10.1038/s41388-023-02628-3