Targeting the NAT10/NPM1 axis abrogates PD-L1 expression and improves the response to immune checkpoint blockade therapy
© 2024. The Author(s)..
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 (Cambridge, Mass.) - 30(2024), 1 vom: 20. Jan., Seite 13 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Qin, Ge [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.01.2024 Date Revised 22.01.2024 published: Electronic Citation Status MEDLINE |
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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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NLM367336650 |
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| 245 | 1 | 0 | |a Targeting the NAT10/NPM1 axis abrogates PD-L1 expression and improves the response to immune checkpoint blockade therapy |
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| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a CONCLUSION: This study suggests that the NAT10/NPM1 axis is a promising therapeutic target in malignant tumors | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Immunotherapy | |
| 650 | 4 | |a NAT10 | |
| 650 | 4 | |a NPM1 | |
| 650 | 4 | |a PD-L1 | |
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| 700 | 1 | |a Bai, Fan |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Huabin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jianwei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhan, Weixiang |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Zehua |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Jianxia |e verfasserin |4 aut | |
| 700 | 1 | |a Fu, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Yanhong |e verfasserin |4 aut | |
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