PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies
PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies
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DOI：
10.1038/nature13561
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发表时间：
2014-10-09
期刊：
影响因子：
64.8
通讯作者：
Cichowski, Karen
中科院分区：
文献类型：
--
作者：
De Raedt, Thomas;Beert, Eline;Cichowski, Karen
多梳抑制复合物2（PRC2）在许多肿瘤类型中发挥致癌作用（1）。然而，PRC2组分的功能丧失突变发生在造血系统恶性肿瘤的一个子集中，表明该复合物在癌症中起着二分法的作用，并且知之甚少（2，3）。在这里，我们提供的基因组，细胞和小鼠模型数据表明，polycomb组基因SUZ12作为肿瘤抑制因子在PNS肿瘤，高级别神经胶质瘤和黑色素瘤的合作，在NF 1突变。NF1编码Ras GTP酶激活蛋白（RasGAP），其丢失通过激活Ras驱动癌症（4）。我们表明，SUZ 12的缺失通过对染色质的影响来放大Ras驱动的转录，从而增强了NF 1突变的影响。然而，重要的是，SUZ12失活还触发了表观遗传开关，使这些癌症对溴结构域抑制剂敏感。总的来说，这些研究不仅揭示了PRC2复合物，NF 1和Ras之间的意想不到的联系，而且还确定了一种有前途的基于表观遗传学的治疗策略，可用于各种癌症。
The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types(1). However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, suggesting that this complex plays a dichotomous and poorly understood role in cancer(2,3). Here we provide genomic, cellular, and mouse modelling data demonstrating that the polycomb group gene SUZ12 functions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras(4). We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhibitors. Collectively, these studies not only reveal an unexpected connection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.