Protein arginine methyltransferase 5 (PRMT5) is a critical oncogenic factor in various cancers, and its inhibition has shown promise in suppressing tumor growth. However, the role of PRMT5 in squamous cell carcinoma (SCC) remains largely unexplored. In this study, we analyzed SCC patient data from The Cancer Genome Atlas (TCGA) and the Cancer Dependency Map (DepMap) to investigate the relationship between PRMT5 and SCC proliferation. We employed competition-based cell proliferation assays, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays, flow cytometry, and in vivo mouse modeling to examine the regulatory roles of PRMT5 and its binding partner WDR77 (WD repeat domain 77). We identified downstream targets, including the p63 isoform ΔNp63α and the cyclin-dependent kinase inhibitor p21, through single-cell RNA-seq, RT-qPCR, and Western blot analyses. Our findings demonstrate that upregulation of PRMT5 and WDR77 correlates with the poor survival of head and neck squamous cell carcinoma (HNSCC) patients. PRMT5/WDR77 regulates the HNSCC-specific transcriptome and facilitates SCC proliferation by promoting cell cycle progression. The PRMT5 and WDR77 stabilize the ΔNp63α Protein, which in turn, inhibits p21. Moreover, depletion of PRMT5 and WDR77 repress SCC in vivo. This study reveals for the first time that PRMT5 and WDR77 synergize to promote SCC proliferation via the ΔNp63α-p21 axis, highlighting a novel therapeutic target for SCC.
蛋白质精氨酸甲基转移酶5（PRMT5）是多种癌症中的关键致癌因子，其抑制在肿瘤生长调控中展现出潜力。然而，PRMT5在鳞状细胞癌（SCC）中的作用机制尚未明确。本研究通过整合癌症基因组图谱（TCGA）和癌症依赖图谱（DepMap）的SCC患者数据，系统探究了PRMT5与SCC增殖的关联。采用竞争性细胞增殖实验、MTT法、流式细胞术及小鼠体内模型，我们解析了PRMT5及其结合蛋白WDR77的调控功能。通过单细胞RNA测序、实时定量PCR和蛋白质印迹分析，鉴定出包括p63异构体ΔNp63α和细胞周期蛋白依赖性激酶抑制剂p21在内的下游靶点。研究结果表明：PRMT5与WDR77的上调与头颈鳞状细胞癌（HNSCC）患者不良预后显著相关；PRMT5/WDR77复合物通过调控HNSCC特异性转录组促进细胞周期进程，从而驱动SCC增殖；该复合物能稳定ΔNp63α蛋白，进而抑制p21表达；体内实验证实敲低PRMT5与WDR77可有效抑制SCC生长。本研究首次揭示PRMT5与WDR77通过ΔNp63α-p21信号轴协同促进SCC增殖的分子机制，为SCC治疗提供了新的潜在靶点。
PRMT5/WDR77 Enhances the Proliferation of Squamous Cell Carcinoma via the ΔNp63α-p21 Axis
肿瘤(癌症)患者之家