1] Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [2] Harvard Medical School, Boston, Massachusetts 02115, USA [3] Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, Massachusetts 02115, USA.
1] Department of Human Genetics, Catholic University Leuven, 3000 Leuven, Belgium [2] [3] Laboratory of Aquatic Biology, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit, Leuven Afdeling Kortrijk, 8500 Kortrijk, Belgium.
Nature. 2014 Oct 9;514(7521):247-51. doi: 10.1038/nature13561. Epub 2014 Aug 13.
The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types. 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. 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. 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.
多梳抑制复合物 2 (PRC2) 在许多肿瘤类型中发挥致癌作用。然而，PRC2 成分的功能丧失性突变发生在一部分血液恶性肿瘤中，这表明该复合物在癌症中发挥着双重且尚未被充分理解的作用。在这里，我们提供了基因组、细胞和小鼠模型数据，证明多梳组基因 SUZ12 通过与 NF1 突变相互作用，在周围神经鞘瘤、高级别神经胶质瘤和黑色素瘤中作为肿瘤抑制因子发挥作用。NF1 编码 Ras GTP 酶激活蛋白 (RasGAP)，其缺失通过激活 Ras 驱动癌症。我们表明，SUZ12 的缺失通过影响染色质来放大 Ras 驱动的转录，从而增强 NF1 突变的效应。然而，重要的是，SUZ12 的失活也触发了一种表观遗传开关，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、NF1 和 Ras 之间的意外联系，而且还确定了一种有前途的基于表观遗传的治疗策略，可能被用于多种癌症。
