Neuroblastoma remains a formidable challenge in pediatric oncology, representing 15% of cancer-related mortalities in children. Despite advancements in combinatorial and targeted treatments improving survival rates, nearly 50% of patients with high-risk neuroblastoma will ultimately succumb to their disease. Dysregulation of the epithelial-mesenchymal transition (EMT) is a key mechanism of tumor cell dissemination, resulting in metastasis and poor outcomes in many cancers. Our prior work identified PRMT5 as a key regulator of EMT via methylation of AKT at arginine 15, enhancing the expression of EMT-driving transcription factors and facilitating metastasis. Here, we identify that PRMT5 directly regulates the transcription of the epidermal growth factor receptor (EGFR). PRMT5, through independent modulation of the EGFR and AKT pathways, orchestrates the activation of NFκB, resulting in the upregulation of the pro-EMT transcription factors ZEB1, SNAIL, and TWIST1. Notably, EGFR and AKT form a compensatory feedback loop, reinforcing the expression of these EMT transcription factors. Small molecule inhibition of PRMT5 methyltransferase activity disrupts EGFR/AKT signaling, suppresses EMT transcription factor expression and ablates tumor growth in vivo. Our findings underscore the pivotal role of PRMT5 in the control of the EMT program in high-risk neuroblastoma.

中文翻译：

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PRMT5协调EGFR和AKT网络激活NFκB并促进EMT

神经母细胞瘤仍然是儿科肿瘤学中的一个巨大挑战，占儿童癌症相关死亡率的 15%。尽管组合和靶向治疗的进步提高了生存率，但近 50% 的高危神经母细胞瘤患者最终将死于该病。上皮间质转化（EMT）失调是肿瘤细胞传播的关键机制，导致许多癌症转移和不良结果。我们之前的工作确定 PRMT5 通过 AKT 精氨酸 15 的甲基化作为 EMT 的关键调节因子，增强 EMT 驱动转录因子的表达并促进转移。在这里，我们确定 PRMT5 直接调节表皮生长因子受体 (EGFR) 的转录。PRMT5 通过独立调节 EGFR 和 AKT 通路，协调 NFκB 的激活，导致促 EMT 转录因子 ZEB1、SNAIL 和 TWIST1 上调。值得注意的是，EGFR 和 AKT 形成补偿反馈环，增强这些 EMT 转录因子的表达。PRMT5 甲基转移酶活性的小分子抑制会破坏 EGFR/AKT 信号传导，抑制 EMT 转录因子表达并消除体内肿瘤生长。我们的研究结果强调了 PRMT5 在控制高危神经母细胞瘤 EMT 程序中的关键作用。