Abstract：
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.
摘要：
蛋白质精氨酸甲基转移酶5（PRMT5）在多种癌症中过表达，并被认为具有关键的致癌作用。部分通过其控制主转录调节因子E2F1来实现。我们调查了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，并与扩增的骨髓细胞瘤病毒相关的癌基因相关。神经母细胞瘤衍生（MYCN）基因。我们的结果表明，MYCN驱动剪接因子基因的表达，与PRMT5和E2F1一起，导致一个去调节的选择性RNA剪接程序，阻止细胞凋亡。PRMT5的药理学抑制或E2F1的失活恢复正常剪接并使NB细胞对凋亡敏感。我们的发现表明，持续的癌症相关的选择性RNA剪接程序使NB细胞对凋亡脱敏，并确定PRMT5作为高危疾病的潜在治疗靶点。
