N4-acetylcytidine modification of ITGB5 mRNA mediated by NAT10 promotes perineural invasion in pancreatic ductal adenocarcinoma
Abstract Background Perineural invasion (PNI) is a hallmark feature of pancreatic ductal adenocarcinoma (PDAC), which occurs at a high incidence and significantly contributes to PDAC lethality and poor survival. Despite its prevalence and association with poor prognosis, the molecular mechanisms und...
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BMC
2025-03-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03362-2 |
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| author | Leyi Huang Yanan Lu Rihua He Xiaofeng Guo Jiajia Zhou Zhiqiang Fu Jingwen Li Jianping Liu Rufu Chen Yu Zhou Quanbo Zhou |
| author_facet | Leyi Huang Yanan Lu Rihua He Xiaofeng Guo Jiajia Zhou Zhiqiang Fu Jingwen Li Jianping Liu Rufu Chen Yu Zhou Quanbo Zhou |
| author_sort | Leyi Huang |
| collection | DOAJ |
| description | Abstract Background Perineural invasion (PNI) is a hallmark feature of pancreatic ductal adenocarcinoma (PDAC), which occurs at a high incidence and significantly contributes to PDAC lethality and poor survival. Despite its prevalence and association with poor prognosis, the molecular mechanisms underlying PNI in PDAC remain unclear. Methods We investigated clinical samples from two cohorts by UPLC/MS-MS to profiled significantly altered chemical RNA modifications in PDAC tissues with PNI lesions. Dorsal root ganglion coculture systems and sciatic nerve injection models validated PNI ability. We combined RNA-seq, acRIP-seq and ac4C-seq with CRISPR-based techniques to explore the regulatory mechanism of ac4C modification on the integrin beta 5 (ITGB5) transcript. Result We reported that N4-acetylcytidine (ac4C) is a significantly altered chemical RNA modification in PDAC tissues with PNI lesions. In vitro and in vivo models demonstrated that tumor cells overexpression of N-acetyltransferase 10 (NAT10), the writer enzyme of mRNA ac4C modification, enhances PNI in PDAC. Further analysis revealed decreased ac4C levels on transcripts of the focal adhesion pathway, particular on ITGB5, in NAT10-knockdown PDAC cells. This ac4C modification in the CDS region of ITGB5 mRNA promotes its stability, subsequently activating the ITGB5-pFAK-pSrc pathway. CRISPR-based analysis further confirmed the crucial role of NAT10-mediated ac4C modification in regulating ITGB5 expression. Combining small-molecule inhibitors targeting NAT10 and focal adhesion kinase (FAK) significantly attenuated PNI in vivo. Conclusion Our findings reveal a previously unrecognized ac4C-mediated epigenetic mechanism in PNI and propose a novel therapeutic strategy to improve survival in PDAC patients. One-sentence summary NAT10 promotes PNI via ac4C modification in PDAC. |
| format | Article |
| id | doaj-art-e1c493e4ac134bd8b452a5f3dabe601a |
| institution | OA Journals |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-e1c493e4ac134bd8b452a5f3dabe601a2025-08-20T01:48:29ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-03-0144111910.1186/s13046-025-03362-2N4-acetylcytidine modification of ITGB5 mRNA mediated by NAT10 promotes perineural invasion in pancreatic ductal adenocarcinomaLeyi Huang0Yanan Lu1Rihua He2Xiaofeng Guo3Jiajia Zhou4Zhiqiang Fu5Jingwen Li6Jianping Liu7Rufu Chen8Yu Zhou9Quanbo Zhou10Department of Pancreas Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityDepartment of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityDepartment of Pancreas Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityGuangzhou Digestive Disease Centre, Guangzhou First People’s Hospital, School of Medicine, South China University of TechnologyGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityZhongshan School of Medicine, Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityDepartment of Pancreas Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityDepartment of Pancreas Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityDepartment of Pancreas Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityAbstract Background Perineural invasion (PNI) is a hallmark feature of pancreatic ductal adenocarcinoma (PDAC), which occurs at a high incidence and significantly contributes to PDAC lethality and poor survival. Despite its prevalence and association with poor prognosis, the molecular mechanisms underlying PNI in PDAC remain unclear. Methods We investigated clinical samples from two cohorts by UPLC/MS-MS to profiled significantly altered chemical RNA modifications in PDAC tissues with PNI lesions. Dorsal root ganglion coculture systems and sciatic nerve injection models validated PNI ability. We combined RNA-seq, acRIP-seq and ac4C-seq with CRISPR-based techniques to explore the regulatory mechanism of ac4C modification on the integrin beta 5 (ITGB5) transcript. Result We reported that N4-acetylcytidine (ac4C) is a significantly altered chemical RNA modification in PDAC tissues with PNI lesions. In vitro and in vivo models demonstrated that tumor cells overexpression of N-acetyltransferase 10 (NAT10), the writer enzyme of mRNA ac4C modification, enhances PNI in PDAC. Further analysis revealed decreased ac4C levels on transcripts of the focal adhesion pathway, particular on ITGB5, in NAT10-knockdown PDAC cells. This ac4C modification in the CDS region of ITGB5 mRNA promotes its stability, subsequently activating the ITGB5-pFAK-pSrc pathway. CRISPR-based analysis further confirmed the crucial role of NAT10-mediated ac4C modification in regulating ITGB5 expression. Combining small-molecule inhibitors targeting NAT10 and focal adhesion kinase (FAK) significantly attenuated PNI in vivo. Conclusion Our findings reveal a previously unrecognized ac4C-mediated epigenetic mechanism in PNI and propose a novel therapeutic strategy to improve survival in PDAC patients. One-sentence summary NAT10 promotes PNI via ac4C modification in PDAC.https://doi.org/10.1186/s13046-025-03362-2Pancreatic ductal adenocarcinomaPerineural invasionRNA ac4C modification |
| spellingShingle | Leyi Huang Yanan Lu Rihua He Xiaofeng Guo Jiajia Zhou Zhiqiang Fu Jingwen Li Jianping Liu Rufu Chen Yu Zhou Quanbo Zhou N4-acetylcytidine modification of ITGB5 mRNA mediated by NAT10 promotes perineural invasion in pancreatic ductal adenocarcinoma Journal of Experimental & Clinical Cancer Research Pancreatic ductal adenocarcinoma Perineural invasion RNA ac4C modification |
| title | N4-acetylcytidine modification of ITGB5 mRNA mediated by NAT10 promotes perineural invasion in pancreatic ductal adenocarcinoma |
| title_full | N4-acetylcytidine modification of ITGB5 mRNA mediated by NAT10 promotes perineural invasion in pancreatic ductal adenocarcinoma |
| title_fullStr | N4-acetylcytidine modification of ITGB5 mRNA mediated by NAT10 promotes perineural invasion in pancreatic ductal adenocarcinoma |
| title_full_unstemmed | N4-acetylcytidine modification of ITGB5 mRNA mediated by NAT10 promotes perineural invasion in pancreatic ductal adenocarcinoma |
| title_short | N4-acetylcytidine modification of ITGB5 mRNA mediated by NAT10 promotes perineural invasion in pancreatic ductal adenocarcinoma |
| title_sort | n4 acetylcytidine modification of itgb5 mrna mediated by nat10 promotes perineural invasion in pancreatic ductal adenocarcinoma |
| topic | Pancreatic ductal adenocarcinoma Perineural invasion RNA ac4C modification |
| url | https://doi.org/10.1186/s13046-025-03362-2 |
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