Acetyltransferase NAT10 inhibits T-cell immunity and promotes nasopharyngeal carcinoma progression through DDX5/HMGB1 axis
Background Immunosuppression significantly contributes to treatment failure in nasopharyngeal carcinoma (NPC). Messenger RNA (mRNA) modifications such as methylation and acetylation play crucial roles in immunosuppression. However, N4-acetylcytidine (ac4C), the only acetylation modification event ha...
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| Language: | English |
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BMJ Publishing Group
2025-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/2/e010301.full |
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| author | Yi Xu Weihong Jiang Rui Wu Siyu Zhang Kaiwen Zhang Haijing Xie Haimeng Yin Si Pan Yumo Han Bo You |
| author_facet | Yi Xu Weihong Jiang Rui Wu Siyu Zhang Kaiwen Zhang Haijing Xie Haimeng Yin Si Pan Yumo Han Bo You |
| author_sort | Yi Xu |
| collection | DOAJ |
| description | Background Immunosuppression significantly contributes to treatment failure in nasopharyngeal carcinoma (NPC). Messenger RNA (mRNA) modifications such as methylation and acetylation play crucial roles in immunosuppression. However, N4-acetylcytidine (ac4C), the only acetylation modification event has rarely been studied in NPC.Methods First, clinical tissue samples and nude mouse models were used to explore the expression of N-acetyltransferase 10 (NAT10) in NPC and its influence on it. Second, The Cancer Genome Atlas immune database and transgenic mouse peripheral blood immune cell panel were used to verify the immune cells mainly affected by NAT10. Then, NAT10 ac4C acetylation modification and expression of significantly upregulated transcription factors were explored by acetylated RNA immunoprecipitation sequence binding to RNA sequencing. Then, the downstream regulatory genes of CCAAT enhancer binding protein γ (CEBPG), dead box helicase 5 (DDX5) and helicase-like transcription factors (HLTF) were analyzed by luciferase report and chromatin Immunoprecipitation. Finally, the effect of inhibition of NAT10 on anti-programmed cell death protein 1 (PD-1) treatment sensitivity was verified by animal models.Results In this study, we aimed to explore the role of NAT10, the enzyme responsible for ac4C modification, in NPC progression and patient prognosis. Elevated NAT10 promoted NPC progression and correlated with poor prognosis in patients with NPC. NAT10-mediated ac4C modification of CEBPG, DDX5, and HLTF mRNA improved their stability and translation efficiency, with the NAT10/ac4C/DDX5 axis upregulating high mobility group box 1 (HMGB1) and inhibiting CD4+ and CD8+ T cells. Inhibition of NAT10 increased the sensitivity to PD-1 therapy. Additionally, HLTF was found to transcriptionally regulate NAT10, indicating the formation of an HLTF-NAT10 positive feedback loop.Conclusions Our study elucidates the mechanism by which the NAT10/DDX5/HMGB1 axis promotes the immunosuppression of NPC by promoting T-cell dysfunction. In addition, NAT10 knockdown can enhance anti-PD-1 treatment sensitivity as a combination therapy for NPC. |
| format | Article |
| id | doaj-art-407f9ba2dc78477daa9880cab28efeee |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-407f9ba2dc78477daa9880cab28efeee2025-08-20T03:31:20ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-02-0113210.1136/jitc-2024-010301Acetyltransferase NAT10 inhibits T-cell immunity and promotes nasopharyngeal carcinoma progression through DDX5/HMGB1 axisYi Xu0Weihong Jiang1Rui Wu2Siyu Zhang3Kaiwen Zhang4Haijing Xie5Haimeng Yin6Si Pan7Yumo Han8Bo You9Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, ChinaNational Clinical Research Center for Geriatric Diseases, Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, ChinaDepartment of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, ChinaDepartment of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, ChinaDepartment of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, ChinaDepartment of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, ChinaDepartment of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, ChinaDepartment of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, ChinaDepartment of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, ChinaBackground Immunosuppression significantly contributes to treatment failure in nasopharyngeal carcinoma (NPC). Messenger RNA (mRNA) modifications such as methylation and acetylation play crucial roles in immunosuppression. However, N4-acetylcytidine (ac4C), the only acetylation modification event has rarely been studied in NPC.Methods First, clinical tissue samples and nude mouse models were used to explore the expression of N-acetyltransferase 10 (NAT10) in NPC and its influence on it. Second, The Cancer Genome Atlas immune database and transgenic mouse peripheral blood immune cell panel were used to verify the immune cells mainly affected by NAT10. Then, NAT10 ac4C acetylation modification and expression of significantly upregulated transcription factors were explored by acetylated RNA immunoprecipitation sequence binding to RNA sequencing. Then, the downstream regulatory genes of CCAAT enhancer binding protein γ (CEBPG), dead box helicase 5 (DDX5) and helicase-like transcription factors (HLTF) were analyzed by luciferase report and chromatin Immunoprecipitation. Finally, the effect of inhibition of NAT10 on anti-programmed cell death protein 1 (PD-1) treatment sensitivity was verified by animal models.Results In this study, we aimed to explore the role of NAT10, the enzyme responsible for ac4C modification, in NPC progression and patient prognosis. Elevated NAT10 promoted NPC progression and correlated with poor prognosis in patients with NPC. NAT10-mediated ac4C modification of CEBPG, DDX5, and HLTF mRNA improved their stability and translation efficiency, with the NAT10/ac4C/DDX5 axis upregulating high mobility group box 1 (HMGB1) and inhibiting CD4+ and CD8+ T cells. Inhibition of NAT10 increased the sensitivity to PD-1 therapy. Additionally, HLTF was found to transcriptionally regulate NAT10, indicating the formation of an HLTF-NAT10 positive feedback loop.Conclusions Our study elucidates the mechanism by which the NAT10/DDX5/HMGB1 axis promotes the immunosuppression of NPC by promoting T-cell dysfunction. In addition, NAT10 knockdown can enhance anti-PD-1 treatment sensitivity as a combination therapy for NPC.https://jitc.bmj.com/content/13/2/e010301.full |
| spellingShingle | Yi Xu Weihong Jiang Rui Wu Siyu Zhang Kaiwen Zhang Haijing Xie Haimeng Yin Si Pan Yumo Han Bo You Acetyltransferase NAT10 inhibits T-cell immunity and promotes nasopharyngeal carcinoma progression through DDX5/HMGB1 axis Journal for ImmunoTherapy of Cancer |
| title | Acetyltransferase NAT10 inhibits T-cell immunity and promotes nasopharyngeal carcinoma progression through DDX5/HMGB1 axis |
| title_full | Acetyltransferase NAT10 inhibits T-cell immunity and promotes nasopharyngeal carcinoma progression through DDX5/HMGB1 axis |
| title_fullStr | Acetyltransferase NAT10 inhibits T-cell immunity and promotes nasopharyngeal carcinoma progression through DDX5/HMGB1 axis |
| title_full_unstemmed | Acetyltransferase NAT10 inhibits T-cell immunity and promotes nasopharyngeal carcinoma progression through DDX5/HMGB1 axis |
| title_short | Acetyltransferase NAT10 inhibits T-cell immunity and promotes nasopharyngeal carcinoma progression through DDX5/HMGB1 axis |
| title_sort | acetyltransferase nat10 inhibits t cell immunity and promotes nasopharyngeal carcinoma progression through ddx5 hmgb1 axis |
| url | https://jitc.bmj.com/content/13/2/e010301.full |
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