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

Thomas De Raedt, Eline Beert, Eric Pasmant, Armelle Luscan, Hilde Brems, Nicolas Ortonne, Kristian Helin, Jason L. Hornick, Victor Mautner, Hildegard Kehrer-Sawatzki, D. Clapp, James Bradner, Michel Vidaud, Meena Upadhyaya, Eric Legius, Karen Cichowski

Research output: Contribution to journalArticle

184 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)247-251
Number of pages5
JournalNature
Volume514
Issue number7521
DOIs
StatePublished - Oct 9 2014

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Polycomb Repressive Complex 2
Neoplasms
Epigenomics
Mutation
Therapeutics
ras GTPase-Activating Proteins
Hematologic Neoplasms
Glioma
Chromatin
Melanoma

ASJC Scopus subject areas

  • General

Cite this

De Raedt, T., Beert, E., Pasmant, E., Luscan, A., Brems, H., Ortonne, N., ... Cichowski, K. (2014). PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature, 514(7521), 247-251. https://doi.org/10.1038/nature13561

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, D.; Bradner, James; Vidaud, Michel; Upadhyaya, Meena; Legius, Eric; Cichowski, Karen.

In: Nature, Vol. 514, No. 7521, 09.10.2014, p. 247-251.

Research output: Contribution to journalArticle

De Raedt, T, Beert, E, Pasmant, E, Luscan, A, Brems, H, Ortonne, N, Helin, K, Hornick, JL, Mautner, V, Kehrer-Sawatzki, H, Clapp, D, Bradner, J, Vidaud, M, Upadhyaya, M, Legius, E & Cichowski, K 2014, 'PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies', Nature, vol. 514, no. 7521, pp. 247-251. https://doi.org/10.1038/nature13561
De Raedt T, Beert E, Pasmant E, Luscan A, Brems H, Ortonne N et al. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-251. https://doi.org/10.1038/nature13561
De Raedt, Thomas ; Beert, Eline ; Pasmant, Eric ; Luscan, Armelle ; Brems, Hilde ; Ortonne, Nicolas ; Helin, Kristian ; Hornick, Jason L. ; Mautner, Victor ; Kehrer-Sawatzki, Hildegard ; Clapp, D. ; Bradner, James ; Vidaud, Michel ; Upadhyaya, Meena ; Legius, Eric ; Cichowski, Karen. / PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. In: Nature. 2014 ; Vol. 514, No. 7521. pp. 247-251.
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