蛋白质精氨酸甲基转移酶 5 (PRMT5) 在多种癌症中过度表达，并被认为具有关键的致癌作用，部分是通过其对主转录调节因子 E2F1 的控制来实现的。我们研究了 PRMT5 和 E2F1 在神经母细胞瘤 (NB) 中的相关性，发现 PRMT5 和 E2F1 的表达升高发生在预后不良的高风险疾病中，并且与扩增的骨髓细胞瘤病毒相关癌基因神经母细胞瘤衍生 (MYCN) 基因相关。我们的结果表明，MYCN 驱动剪接因子基因的表达，这些剪接因子基因与 PRMT5 和 E2F1 一起，导致替代性 RNA 剪接程序失调，从而阻碍细胞凋亡。 PRMT5 的药理学抑制或 E2F1 的失活可恢复正常剪接并使 NB 细胞对细胞凋亡敏感。我们的研究结果表明，持续的癌症相关替代 RNA 剪接程序会使 NB 细胞对细胞凋亡脱敏，并将 PRMT5 确定为高风险疾病的潜在治疗靶点。© 2024 作者。约翰·威利出版的《分子肿瘤学》

Protein arginine methyltransferase 5 (PRMT5) is over-expressed in a wide variety of cancers and is implicated as having a key oncogenic role, achieved in part through its control of the master transcription regulator E2F1. We investigated the relevance of PRMT5 and E2F1 in neuroblastoma (NB) and found that elevated expression of PRMT5 and E2F1 occurs in poor prognosis high-risk disease and correlates with an amplified Myelocytomatosis viral-related oncogene, neuroblastoma-derived (MYCN) gene. Our results show that MYCN drives the expression of splicing factor genes that, together with PRMT5 and E2F1, lead to a deregulated alternative RNA splicing programme that impedes apoptosis. Pharmacological inhibition of PRMT5 or inactivation of E2F1 restores normal splicing and renders NB cells sensitive to apoptosis. Our findings suggest that a sustained cancer-relevant alternative RNA splicing programme desensitises NB cells to apoptosis, and identify PRMT5 as a potential therapeutic target for high-risk disease.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.