Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA.
Epizyme, Inc., Cambridge, MA, USA.
Sci Rep. 2018 Jun 26;8(1):9711. doi: 10.1038/s41598-018-28002-y.
Evasion of the potent tumour suppressor activity of p53 is one of the hurdles that must be overcome for cancer cells to escape normal regulation of cellular proliferation and survival. In addition to frequent loss of function mutations, p53 wild-type activity can also be suppressed post-translationally through several mechanisms, including the activity of PRMT5. Here we describe broad anti-proliferative activity of potent, selective, reversible inhibitors of protein arginine methyltransferase 5 (PRMT5) including GSK3326595 in human cancer cell lines representing both hematologic and solid malignancies. Interestingly, PRMT5 inhibition activates the p53 pathway via the induction of alternative splicing of MDM4. The MDM4 isoform switch and subsequent p53 activation are critical determinants of the response to PRMT5 inhibition suggesting that the integrity of the p53-MDM4 regulatory axis defines a subset of patients that could benefit from treatment with GSK3326595.
逃避强效肿瘤抑制因子 p53 的活性是癌细胞逃避细胞增殖和存活的正常调控所必须克服的障碍之一。除了频繁的功能丧失突变外，p53 野生型活性还可以通过几种机制进行翻译后抑制，包括 PRMT5 的活性。在这里，我们描述了强效、选择性、可逆的蛋白质精氨酸甲基转移酶 5（PRMT5）抑制剂，包括 GSK3326595，在代表血液系统和实体恶性肿瘤的人类癌细胞系中的广泛抗增殖活性。有趣的是，PRMT5 抑制通过诱导 MDM4 的选择性剪接激活 p53 途径。MDM4 异构体转换和随后的 p53 激活是对 PRMT5 抑制反应的关键决定因素，这表明 p53-MDM4 调节轴的完整性定义了可以从 GSK3326595 治疗中获益的患者亚组。
