Nasopharyngeal carcinoma (NPC) is a tumor deriving from nasopharyngeal epithelium. Peptidyl-arginine deiminase 4 (PAD4) is a vital mediator of histone citrullination and plays an essential role in regulating disease process. Radiotherapy is an essential method to treat NPC. In this research, we explored the effect of PAD4 on NPC radiosensitivity. We enrolled 50 NPC patients, established mice xenograft model, and purchased cell lines for this study. Statistical analysis and a series of experiments including RT-qPCR, clonogenic survival, EdU, Transwell, and wound healing assays were done. Our data manifested that PAD4 (mRNA and protein) presented a high expression in NPC tissues and cells. GSK484, an inhibitor of PAD4, could inhibit activity of PAD4 in NPC cell lines. PAD4 overexpression promoted the radioresistance, survival, migration, and invasion of NPC cells, whereas treatment of GSK484 exerted inhibitory effects on radioresistance and aggressive phenotype of NPC cells. Additionally, GSK484 could attenuate the effect of PAD4 of NPC cell progression. More importantly, we found that GSK484 significantly inhibited tumor size, tumor weight and tumor volume in mice following irradiation. PAD4 inhibitor GSK484 attenuated the radioresistance and cellular progression in NPC.

中文翻译：

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抑制 PAD4 可增强放射敏感性并抑制鼻咽癌细胞的侵袭性表型

鼻咽癌（NPC）是起源于鼻咽上皮细胞的肿瘤。肽基精氨酸脱亚胺酶 4 (PAD4) 是组蛋白瓜氨酸化的重要介质，在调节疾病过程中起着重要作用。放射治疗是治疗鼻咽癌的重要手段。在这项研究中，我们探讨了 PAD4 对鼻咽癌放射敏感性的影响。我们招募了 50 名 NPC 患者，建立了小鼠异种移植模型，并为这项研究购买了细胞系。进行了统计分析和一系列实验，包括 RT-qPCR、克隆形成存活、EdU、Transwell 和伤口愈合测定。我们的数据表明 PAD4（mRNA 和蛋白质）在 NPC 组织和细胞中呈高表达。GSK484 是一种 PAD4 抑制剂，可抑制 NPC 细胞系中 PAD4 的活性。PAD4过表达促进了放射抗性、存活、迁移、和 NPC 细胞的侵袭，而 GSK484 的处理对 NPC 细胞的放射抗性和侵袭性表型产生抑制作用。此外，GSK484 可以减弱 PAD4 对 NPC 细胞进展的影响。更重要的是，我们发现 GSK484 显着抑制了照射后小鼠的肿瘤大小、肿瘤重量和肿瘤体积。PAD4 抑制剂 GSK484 减弱了 NPC 中的放射抗性和细胞进展。