Aberrant expression of protein arginine methyltransferases (PRMTs) has been implicated in a number of cancers, making PRMTs potential therapeutic targets. But it remains not well understood how PRMTs impact specific oncogenic pathways. We previously identified PRMTs as important regulators of cell growth in neuroblastoma, a deadly childhood tumor of the sympathetic nervous system. Here, we demonstrate a critical role for PRMT1 in neuroblastoma cell survival. PRMT1 depletion decreased the ability of murine neuroblastoma sphere cells to grow and form spheres, and suppressed proliferation and induced apoptosis of human neuroblastoma cells. Mechanistic studies reveal the prosurvival factor, activating transcription factor 5 (ATF5) as a downstream effector of PRMT1-mediated survival signaling. Furthermore, a diamidine class of PRMT1 inhibitors exhibited anti-neuroblastoma efficacy both in vitro and in vivo. Importantly, overexpression of ATF5 rescued cell apoptosis triggered by PRMT1 inhibition genetically or pharmacologically. Taken together, our findings shed new insights into PRMT1 signaling pathway, and provide evidence for PRMT1 as an actionable therapeutic target in neuroblastoma.

中文翻译：

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PRMT1 通过 ATF5 促进神经母细胞瘤细胞存活。


蛋白质精氨酸甲基转移酶 (PRMT) 的异常表达与许多癌症有关，这使得 PRMT 成为潜在的治疗靶点。但目前尚不清楚 PRMT 如何影响特定的致癌途径。我们之前发现 PRMT 是神经母细胞瘤细胞生长的重要调节因子，神经母细胞瘤是一种致命的儿童交感神经系统肿瘤。在这里，我们证明了 PRMT1 在神经母细胞瘤细胞存活中的关键作用。 PRMT1缺失降低了小鼠神经母细胞瘤球细胞生长和形成球体的能力，并抑制了人神经母细胞瘤细胞的增殖并诱导细胞凋亡。机制研究揭示了促生存因子、激活转录因子 5 (ATF5) 作为 PRMT1 介导的生存信号传导的下游效应子。此外，二脒类 PRMT1 抑制剂在体外和体内均表现出抗神经母细胞瘤功效。重要的是，ATF5 的过度表达可以从基因或药理学角度挽救 PRMT1 抑制引发的细胞凋亡。总而言之，我们的研究结果为 PRMT1 信号通路提供了新的见解，并为 PRMT1 作为神经母细胞瘤的可行治疗靶点提供了证据。