title: Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis.
abstract: Alterations of chromatin modifiers are frequent in cancer, but their functional consequences often remain unclear. Focusing on the Polycomb protein EZH2 that deposits the H3K27me3 (trimethylation of Lys27 of histone H3) mark, we showed that its high expression in solid tumors is a consequence, not a cause, of tumorigenesis. In mouse and human models, EZH2 is dispensable for prostate cancer development and restrains breast tumorigenesis. High EZH2 expression in tumors results from a tight coupling to proliferation to ensure H3K27me3 homeostasis. However, this process malfunctions in breast cancer. Low EZH2 expression relative to proliferation and mutations in Polycomb genes actually indicate poor prognosis and occur in metastases. We show that while altered EZH2 activity consistently modulates a subset of its target genes, it promotes a wider transcriptional instability. Importantly, transcriptional changes that are consequences of EZH2 loss are predominantly irreversible. Our study provides an unexpected understanding of EZH2's contribution to solid tumors with important therapeutic implications.
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France; U934, Institut National de la Santé et de la Recherche Médicale, 75005 Paris, France; UMR3215, Centre National de la Recherche Scientifique, 75005 Paris, France;
authors.forename: Michel
authors.initials: M
authors.lastname: Wassef
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France; U934, Institut National de la Santé et de la Recherche Médicale, 75005 Paris, France; UMR3215, Centre National de la Recherche Scientifique, 75005 Paris, France;
authors.forename: Veronica
authors.initials: V
authors.lastname: Rodilla
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France; U900, Institut National de la Santé et de la Recherche Médicale, 75005 Paris, France; Mines ParisTech, 77300 Fontainebleau, France;
authors.forename: Aurélie
authors.initials: A
authors.lastname: Teissandier
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France; U900, Institut National de la Santé et de la Recherche Médicale, 75005 Paris, France; Mines ParisTech, 77300 Fontainebleau, France;
authors.forename: Bruno
authors.initials: B
authors.lastname: Zeitouni
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France;
authors.forename: Nadege
authors.initials: N
authors.lastname: Gruel
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Sadacca
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France;
authors.forename: Marie
authors.initials: M
authors.lastname: Irondelle
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France; U934, Institut National de la Santé et de la Recherche Médicale, 75005 Paris, France; UMR3215, Centre National de la Recherche Scientifique, 75005 Paris, France;
authors.forename: Margaux
authors.initials: M
authors.lastname: Charruel
authors.affiliation: Laboratoire de Physique Statistique-Ecole Normale Supérieure de Paris, Centre National de la Recherche Scientifique, 75005 Paris, France; UMR 8550, Centre National de la Recherche Scientifique, 75005 Paris, France; Plateforme de PCR Quantitative à Haut Débit Genomic Paris Centre, Institut de Biologie de l'École Normale Supérieure, 75005 Paris, France;
authors.forename: Bertrand
authors.initials: B
authors.lastname: Ducos
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France; U934, Institut National de la Santé et de la Recherche Médicale, 75005 Paris, France; UMR3215, Centre National de la Recherche Scientifique, 75005 Paris, France;
authors.forename: Audrey
authors.initials: A
authors.lastname: Michaud
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France; U934, Institut National de la Santé et de la Recherche Médicale, 75005 Paris, France; UMR3215, Centre National de la Recherche Scientifique, 75005 Paris, France;
authors.forename: Matthieu
authors.initials: M
authors.lastname: Caron
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France;
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Chavrier
authors.affiliation: Department of Medical Oncology, Institut Curie, 75005 Paris, France; EA7285, Université de Versailles, Saint-Quentin-en-Yvelines, 78000 Versailles, France;
authors.forename: Christophe
authors.initials: C
authors.lastname: Le Tourneau
authors.affiliation: Department of Medical Oncology, Institut Curie, 75005 Paris, France;
authors.forename: Maud
authors.initials: M
authors.lastname: Kamal
authors.affiliation: UMR_S745, EA7331, Institut National de la Santé et de la Recherche Médicale, 75006 Paris, France; Facultée des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Service de Biochimie et Génétique Moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, 75014 Paris, France;
authors.forename: Eric
authors.initials: E
authors.lastname: Pasmant
authors.affiliation: UMR_S745, EA7331, Institut National de la Santé et de la Recherche Médicale, 75006 Paris, France; Facultée des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Service de Biochimie et Génétique Moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, 75014 Paris, France;
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France; U900, Institut National de la Santé et de la Recherche Médicale, 75005 Paris, France; Mines ParisTech, 77300 Fontainebleau, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Servant
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France;
authors.forename: Fabien
authors.initials: F
authors.lastname: Reyal
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France; Platform of Investigative Pathology, 75005 Paris, France.
authors.forename: Dider
authors.initials: D
authors.lastname: Meseure
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France;
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France; U934, Institut National de la Santé et de la Recherche Médicale, 75005 Paris, France; UMR3215, Centre National de la Recherche Scientifique, 75005 Paris, France;
authors.forename: Silvia
authors.initials: S
authors.lastname: Fre
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, 75005 Paris, France; U934, Institut National de la Santé et de la Recherche Médicale, 75005 Paris, France; UMR3215, Centre National de la Recherche Scientifique, 75005 Paris, France;
authors.forename: Raphaël
authors.initials: R
authors.lastname: Margueron
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001943:Breast Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008297:Male; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics
chemical_list: D006657:Histones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2
keywords: EZH2; Polycomb; cancer; chromatin