<br>NAT10/ac4C/FOXP1 通过重编程宫颈癌的糖酵解代谢促进恶性进展并促进免疫抑制,Advanced Science

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NAT10/ac4C/FOXP1 通过重编程宫颈癌的糖酵解代谢促进恶性进展并促进免疫抑制
Advanced Science ( IF 14.3 ) Pub Date : 2023-10-11 , DOI: 10.1002/advs.202302705
Xiaona Chen _{1,

2} , Yi Hao ₃ , Yong Liu ₄ , Sheng Zhong _{1,

2} , Yuehua You _{5,

6} , Keyi Ao _{1,

2} , Tuotuo Chong _{1,

2} , Xiaomin Luo _{1,

2} , Minuo Yin ₇ , Ming Ye ₈ , Hui He ₉ , Anwei Lu ₇ , Jianjun Chen ₁₀ , Xin Li _{1,

2} , Jian Zhang _{11,

12} , Xia Guo _{1,

2}

Affiliation

Shenzhen Key Laboratory of Viral Oncology; Ministry of Science and Innovation, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China.
The Third School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China.
Department of Ultrasound, South China Hospital of Shenzhen University, Shenzhen, Guangdong, China.
Department of Critical Care Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China.
Department of Stomatology, Longhua People's Hospital Affiliated with Southern Medical University, Shenzhen, Guangdong, China.
School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China.
Department of Obstetrics and Gynecology, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, China.
Department of Pathology, Affiliated Tumour Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
Department of Pathology, Shenzhen Hospital, The University of Hong Kong, Shenzhen, Guangdong, China.
School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, Guangdong, China.
School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China.
Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen, Guangdong, China.

免疫疗法最近已成为宫颈癌（CCa）的主要治疗方法，受到免疫检查点抑制剂（ICI）（如抗 PD-1/PD-L1 抗体）突破性临床成就的推动。由 NAT10 催化的 N4-乙酰胞苷（ac4C）修饰是癌症中 mRNA 的重要转录后修饰。然而，它对 CCa 中免疫失调和肿瘤免疫治疗反应的影响仍然是个谜。在这里，最初观察到 CCa 组织中 NAT10 表达的显着增加，这在临床上与不良预后相关。随后发现 HOXC8 通过与启动子结合激活 NAT10，从而刺激 FOXP1 mRNA 的 ac4C 修饰并提高其翻译效率，最终导致 GLUT4 和 KHK 表达的诱导。此外，NAT10/ac4C/FOXP1 轴活性导致 CCa 细胞糖酵解增加和乳酸分泌持续增加。富含乳酸的肿瘤微环境（TME）进一步有助于放大肿瘤浸润调节性 T 细胞（Tregs）的免疫抑制特性。令人印象深刻的是，NAT10 敲低增强了 PD-L1 阻断介导的体内肿瘤消退的疗效。综上所述，研究结果揭示了 NAT10 在启动癌细胞糖酵解和免疫抑制之间的串扰中的致癌作用，这可能是 CCa 中协同 PD-1/PD-L1 阻断免疫治疗的靶点。

"点击查看英文标题和摘要"

NAT10/ac4C/FOXP1 Promotes Malignant Progression and Facilitates Immunosuppression by Reprogramming Glycolytic Metabolism in Cervical Cancer

Immunotherapy has recently emerged as the predominant therapeutic approach for cervical cancer (CCa), driven by the groundbreaking clinical achievements of immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1 antibodies. N4-acetylcytidine (ac4C) modification, catalyzed by NAT10, is an important posttranscriptional modification of mRNA in cancers. However, its impact on immunological dysregulation and the tumor immunotherapy response in CCa remains enigmatic. Here, a significant increase in NAT10 expression in CCa tissues is initially observed that is clinically associated with poor prognosis. Subsequently, it is found that HOXC8 activated NAT10 by binding to its promoter, thereby stimulating ac4C modification of FOXP1 mRNA and enhancing its translation efficiency, eventually leading to induction of GLUT4 and KHK expression. Moreover, NAT10/ac4C/FOXP1 axis activity resulted in increased glycolysis and a continuous increase in lactic acid secretion by CCa cells. The lactic acid-enriched tumor microenvironment (TME) further contributed to amplifying the immunosuppressive properties of tumor-infiltrating regulatory T cells (Tregs). Impressively, NAT10 knockdown enhanced the efficacy of PD-L1 blockade-mediated tumor regression in vivo. Taken together, the findings revealed the oncogenic role of NAT10 in initiating crosstalk between cancer cell glycolysis and immunosuppression, which can be a target for synergistic PD-1/PD-L1 blockade immunotherapy in CCa.

更新日期：2023-10-11

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