Liang Heng, Fisher Matthew L, Wu Caizhi, Ballon Carlos, Sun Xueqin, Mills Alea A
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Molecular and Cell Biology Graduate Program, Stony Brook University, Stony Brook, NY 11794, USA.
Cancers (Basel). 2024 Nov 11;16(22):3789. doi: 10.3390/cancers16223789.
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，抑制该酶已显示出抑制肿瘤生长的潜力。然而，PRMT5在鳞状细胞癌（SCC）中的作用在很大程度上仍未得到探索。在本研究中，我们分析了来自癌症基因组图谱（TCGA）和癌症依赖性图谱（DepMap）的SCC患者数据，以研究PRMT5与SCC增殖之间的关系。我们采用基于竞争的细胞增殖试验、3-（4,5-二甲基噻唑-2-基）-2,5-二苯基-2H-四唑溴盐（MTT）试验、流式细胞术和体内小鼠模型，来研究PRMT5及其结合伴侣WDR77（WD重复结构域77）的调控作用。我们通过单细胞RNA测序、RT-qPCR和蛋白质免疫印迹分析，确定了包括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。我们的研究结果表明，PRMT5和WDR77的上调与头颈部鳞状细胞癌（HNSCC）患者的不良生存相关。PRMT5/WDR77调节HNSCC特异性转录组，并通过促进细胞周期进程来促进SCC增殖。PRMT5和WDR77稳定ΔNp63α蛋白，进而抑制p21。此外，PRMT5和WDR77的缺失在体内可抑制SCC。本研究首次揭示PRMT5和WDR77通过ΔNp63α-p21轴协同促进SCC增殖，突出了SCC的一个新的治疗靶点。
