Publication Date:
2014-08-15
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- Cichowski, Karen -- England -- Nature. 2014 Oct 9;514(7521):247-51. doi: 10.1038/nature13561. Epub 2014 Aug 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; 1] INSERM UMR_S745 et EA7331, Universite Paris Descartes, Sorbonne Paris Cite, Faculte des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France [2] Service de Biochimie et Genetique Moleculaire, Hopital Cochin, Assistance Publique-Hopitaux de Paris, 75014 Paris, France [3]. ; 1] INSERM UMR_S745 et EA7331, Universite Paris Descartes, Sorbonne Paris Cite, Faculte des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France [2] Service de Biochimie et Genetique Moleculaire, Hopital Cochin, Assistance Publique-Hopitaux de Paris, 75014 Paris, France. ; Department of Human Genetics, Catholic University Leuven, 3000 Leuven, Belgium. ; 1] Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark [2] Center for Epigenetics, University of Copenhagen, 2200 Copenhagen, Denmark [3] The Danish Stem Cell Center (Danstem), University of Copenhagen, 2200 Copenhagen, Denmark. ; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; Department of Maxillofacial Surgery, University Medical Centre, Hamburg-Eppendorf, 20246 Hamburg, Germany. ; Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany. ; Herman Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 46202 Indianapolis, Indiana, USA. ; 1] Harvard Medical School, Boston, Massachusetts 02115, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Massachusetts 02115, USA. ; Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. ; 1] Department of Human Genetics, Catholic University Leuven, 3000 Leuven, Belgium [2] Center for Human Genetics, University Hospital Leuven, 3000 Leuven Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119042" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Azepines/pharmacology/therapeutic use
;
Cell Death/drug effects
;
Chromatin/drug effects/genetics/metabolism
;
Disease Models, Animal
;
Epigenesis, Genetic/drug effects
;
Gene Expression Regulation, Neoplastic/drug effects
;
Glioma/drug therapy/genetics/pathology
;
Humans
;
Melanoma/drug therapy/genetics/pathology
;
Mice
;
Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors
;
Neoplasms/*drug therapy/*genetics/pathology
;
Nerve Sheath Neoplasms/drug therapy/genetics/pathology
;
Neurofibromin 1/deficiency/genetics
;
Nuclear Proteins/*antagonists & inhibitors/deficiency/genetics/metabolism
;
Polycomb Repressive Complex 2/*deficiency/genetics/metabolism
;
Transcription Factors/*antagonists & inhibitors/deficiency/genetics/metabolism
;
*Transcription, Genetic/drug effects
;
Triazoles/pharmacology/therapeutic use
;
Tumor Suppressor Proteins/deficiency/genetics/metabolism
;
ras Proteins/antagonists & inhibitors/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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