Targeting the NAT10/NPM1 axis abrogates PD-L1 expression and improves the response to immune checkpoint blockade therapy
Background PD-1/PD-L1 play a crucial role as immune checkpoint inhibitors in various types of cancer. Although our previous study revealed that NPM1 was a novel transcriptional regulator of PD-L1 and stimulated the transcription of PD-L1, the underlying regulatory mechanism remains incompletely characterized. Methods Various human cancer cell lines were used to validate the role of NPM1 in regulating the transcription of PD-L1. The acetyltransferase NAT10 was identified as a facilitator of NPM1 acetylation by coimmunoprecipitation and mass spectrometry. The potential application of combined NAT10 inhibitor and anti-CTLA4 treatment was evaluated by an animal model. Results We demonstrated that NPM1 enhanced the transcription of PD-L1 in various types of cancer, and the acetylation of NPM1 played a vital role in this process. In particular, NAT10 facilitated the acetylation of NPM1, leading to enhanced transcription and increased expression of PD-L1. Moreover, our findings demonstrated that Remodelin, a compound that inhibits NAT10, effectively reduced NPM1 acetylation, leading to a subsequent decrease in PD-L1 expression. In vivo experiments indicated that Remodelin combined with anti-CTLA-4 therapy had a superior therapeutic effect compared with either treatment alone. Ultimately, we verified that the expression of NAT10 exhibited a positive correlation with the expression of PD-L1 in various types of tumors, serving as an indicator of unfavorable prognosis. Conclusion This study suggests that the NAT10/NPM1 axis is a promising therapeutic target in malignant tumors..
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2024 |
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Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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Enthalten in: |
Molecular medicine - 30(2024), 1 vom: 20. Jan. |
Sprache: |
Englisch |
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Beteiligte Personen: |
Qin, Ge [VerfasserIn] |
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Links: |
Volltext [kostenfrei] |
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Themen: |
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Anmerkungen: |
© The Author(s) 2024 |
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doi: |
10.1186/s10020-024-00780-4 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
SPR054445892 |
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520 | |a Background PD-1/PD-L1 play a crucial role as immune checkpoint inhibitors in various types of cancer. Although our previous study revealed that NPM1 was a novel transcriptional regulator of PD-L1 and stimulated the transcription of PD-L1, the underlying regulatory mechanism remains incompletely characterized. Methods Various human cancer cell lines were used to validate the role of NPM1 in regulating the transcription of PD-L1. The acetyltransferase NAT10 was identified as a facilitator of NPM1 acetylation by coimmunoprecipitation and mass spectrometry. The potential application of combined NAT10 inhibitor and anti-CTLA4 treatment was evaluated by an animal model. Results We demonstrated that NPM1 enhanced the transcription of PD-L1 in various types of cancer, and the acetylation of NPM1 played a vital role in this process. In particular, NAT10 facilitated the acetylation of NPM1, leading to enhanced transcription and increased expression of PD-L1. Moreover, our findings demonstrated that Remodelin, a compound that inhibits NAT10, effectively reduced NPM1 acetylation, leading to a subsequent decrease in PD-L1 expression. In vivo experiments indicated that Remodelin combined with anti-CTLA-4 therapy had a superior therapeutic effect compared with either treatment alone. Ultimately, we verified that the expression of NAT10 exhibited a positive correlation with the expression of PD-L1 in various types of tumors, serving as an indicator of unfavorable prognosis. Conclusion This study suggests that the NAT10/NPM1 axis is a promising therapeutic target in malignant tumors. | ||
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700 | 1 | |a Bai, Fan |4 aut | |
700 | 1 | |a Hu, Huabin |4 aut | |
700 | 1 | |a Zhang, Jianwei |4 aut | |
700 | 1 | |a Zhan, Weixiang |4 aut | |
700 | 1 | |a Wu, Zehua |4 aut | |
700 | 1 | |a Li, Jianxia |4 aut | |
700 | 1 | |a Fu, Yang |4 aut | |
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