Article

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

Nature, Springer Nature, ISSN 1476-4687

Volume 514, 7521, 2014

DOI:10.1038/nature13561, Dimensions: pub.1053323056, PMID: 25119042,

Authors

De Raedt, Thomas (1) (2) (3)
Pasmant, Eric (5) (6)
Luscan, Armelle (5) (6)
Bradner, James (1) (11)
Vidaud, Michel (5) (6)
Legius, Eric * (4) (13)
Cichowski, Karen * (1) (2) (3)

* Corresponding author

Affiliations

Organisations

  1. (1) Harvard University, grid.38142.3c
  2. (2) Dana-Farber/Harvard Cancer Center, grid.477947.e
  3. (3) Brigham and Women's Hospital, grid.62560.37
  4. (4) KU Leuven, grid.5596.f
  5. (5) Hôpital Cochin, grid.411784.f
  6. (6) Paris Descartes University, grid.10992.33
  7. (7) University of Copenhagen, grid.5254.6, KU
  8. (8) University Medical Center Hamburg-Eppendorf, grid.13648.38
  9. (9) University of Ulm, grid.6582.9
  10. (10) Indiana University – Purdue University Indianapolis, grid.257413.6
  11. (11) Dana-Farber Cancer Institute, grid.65499.37
  12. (12) Cardiff University, grid.5600.3
  13. (13) Center for Human Genetics, University Hospital Leuven, 3000 Leuven Belgium

Description

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.

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University of Copenhagen

Danish Open Access Indicator

2014: Unused

Research area: Science & Technology

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2014: Level 2

Research area: Science & Technology

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Times Cited: 242

Field Citation Ratio (FCR): 38.77

Relative Citation ratio (RCR): 7.33