title: PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies.
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.
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: De Raedt
authors.affiliation: 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.
authors.forename: Eline
authors.initials: E
authors.lastname: Beert
authors.affiliation: 1] INSERM UMR_S745 et EA7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France [2] Service de Biochimie et Génétique Moléculaire, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France [3].
authors.forename: Eric
authors.initials: E
authors.lastname: Pasmant
authors.affiliation: 1] INSERM UMR_S745 et EA7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France [2] Service de Biochimie et Génétique Moléculaire, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Luscan
authors.affiliation: Department of Human Genetics, Catholic University Leuven, 3000 Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Brems
authors.affiliation: 1] INSERM UMR_S745 et EA7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France [2] Service de Biochimie et Génétique Moléculaire, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ortonne
authors.affiliation: 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.
authors.forename: Kristian
authors.initials: K
authors.lastname: Helin
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.affiliation: Department of Maxillofacial Surgery, University Medical Centre, Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Victor
authors.initials: V
authors.lastname: Mautner
authors.affiliation: Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany.
authors.forename: Hildegard
authors.initials: H
authors.lastname: Kehrer-Sawatzki
authors.affiliation: Herman Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 46202 Indianapolis, Indiana, USA.
authors.forename: Wade
authors.initials: W
authors.lastname: Clapp
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts 02115, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Massachusetts 02115, USA.
authors.forename: James
authors.initials: J
authors.lastname: Bradner
authors.affiliation: 1] INSERM UMR_S745 et EA7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France [2] Service de Biochimie et Génétique Moléculaire, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.affiliation: Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Meena
authors.initials: M
authors.lastname: Upadhyaya
authors.affiliation: 1] Department of Human Genetics, Catholic University Leuven, 3000 Leuven, Belgium [2] Center for Human Genetics, University Hospital Leuven, 3000 Leuven Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Legius
authors.affiliation: 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.
authors.forename: Karen
authors.initials: K
authors.lastname: Cichowski
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000187:drug effects; D002843:Chromatin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D025542:Neurofibromin 1 / Q000172:deficiency / Q000235:genetics; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D002843:Chromatin; D020929:Mitogen-Activated Protein Kinase Kinases; D009363:Neoplasm Proteins; D025542:Neurofibromin 1; D009687:Nuclear Proteins; D063151:Polycomb Repressive Complex 2; D014157:Transcription Factors; D014230:Triazoles; D025521:Tumor Suppressor Proteins; D018631:ras Proteins; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C430461:SUZ12 protein, human; C494163:Suz12 protein, mouse