Scholarlink

Background <p>N-acetyltransferase 10 (NAT10) mediated N4-acetylcytidine (ac4C) modification has been implicated in tumor progression; however, the precise role and underlying mechanism of NAT10 in breast cancer progression remain largely undefined.</p> Methods <p>The expression and prognostic significance of NAT10 in breast cancer were evaluated using clinical tissue samples and public databases. Functional assays were performed in vitro and in vivo to assess the effects of NAT10 on tumor growth and immune evasion. Mechanistic studies, including RNA immunoprecipitation (RIP), ac4C RNA immunoprecipitation (acRIP), and co-immunoprecipitation (Co-IP), were conducted to elucidate the interaction between NAT10 and histone deacetylase 4 (HDAC4) and their roles in regulating NF-κB signaling and programmed death-ligand 1 (PD-L1) expression.</p> Results <p>NAT10 expression was significantly upregulated in breast cancer and correlated with poor patient prognosis. NAT10 mediated ac4C modification enhanced the stability of HDAC4 mRNA, thereby promoting HDAC4 expression. Conversely, HDAC4 stabilized NAT10 protein through post-transcriptional deacetylation, forming a self-reinforcing regulatory loop. Elevated HDAC4 activated the NF-κB signaling pathway, resulting in increased PD-L1 transcription and enhanced immune evasion of breast cancer cells. Inhibition of the NAT10/HDAC4/NF-κB axis markedly reduced PD-L1 expression and restored antitumor immune responses.</p> Conclusion <p>Our findings identify a self-reinforcing NAT10/HDAC4 signaling circuit that drives breast cancer progression and immune evasion. Targeting NAT10 represents a promising therapeutic strategy to overcome immunosuppression and improve patient outcomes in breast cancer.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Targeting the NAT10-HDAC4 positive feedback loop counteracts immunosuppression in breast cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月7日

查看全文
  • Xin Ma,
  • Shengye Jin,
  • Xingda Zhang,
  • Liuying Zhao,
  • Haoran Wang,
  • Siyu Liu,
  • Hui Li,
  • Qin Wang,
  • Song Gao,
  • Jianyu Wang,
  • Yajie Gong,
  • Yijun Chu,
  • Crystal Song Zhang,
  • Xi Chen,
  • Da Pang,
  • Cheng Qian,
  • Hao Wu

摘要

Background

N-acetyltransferase 10 (NAT10) mediated N4-acetylcytidine (ac4C) modification has been implicated in tumor progression; however, the precise role and underlying mechanism of NAT10 in breast cancer progression remain largely undefined.

Methods

The expression and prognostic significance of NAT10 in breast cancer were evaluated using clinical tissue samples and public databases. Functional assays were performed in vitro and in vivo to assess the effects of NAT10 on tumor growth and immune evasion. Mechanistic studies, including RNA immunoprecipitation (RIP), ac4C RNA immunoprecipitation (acRIP), and co-immunoprecipitation (Co-IP), were conducted to elucidate the interaction between NAT10 and histone deacetylase 4 (HDAC4) and their roles in regulating NF-κB signaling and programmed death-ligand 1 (PD-L1) expression.

Results

NAT10 expression was significantly upregulated in breast cancer and correlated with poor patient prognosis. NAT10 mediated ac4C modification enhanced the stability of HDAC4 mRNA, thereby promoting HDAC4 expression. Conversely, HDAC4 stabilized NAT10 protein through post-transcriptional deacetylation, forming a self-reinforcing regulatory loop. Elevated HDAC4 activated the NF-κB signaling pathway, resulting in increased PD-L1 transcription and enhanced immune evasion of breast cancer cells. Inhibition of the NAT10/HDAC4/NF-κB axis markedly reduced PD-L1 expression and restored antitumor immune responses.

Conclusion

Our findings identify a self-reinforcing NAT10/HDAC4 signaling circuit that drives breast cancer progression and immune evasion. Targeting NAT10 represents a promising therapeutic strategy to overcome immunosuppression and improve patient outcomes in breast cancer.