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PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies

De Raedt, Thomas, Beert, Eline, Pasmant, Eric, Luscan, Armelle, Brems, Hilde, Ortonne, Nicolas, Helin, Kristian, Hornick, Jason L., Mautner, Victor, Kehrer-Sawatzki, Hildegard, Clapp, Wade, Bradner, James, Vidaud, Michel, Upadhyaya, Meena, Legius, Eric and Cichowski, Karen 2014. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 514 (7521) , pp. 247-251. 10.1038/nature13561

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Abstract

The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types1. 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 cancer2, 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 Ras4. 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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: Tumour suppressors; Cancer models; Targeted therapies
Publisher: Nature Publishing Group
ISSN: 0028-0836
Date of Acceptance: 6 June 2014
Last Modified: 04 Jun 2017 09:07
URI: http://orca.cf.ac.uk/id/eprint/90761

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