title: The breast cancer oncogene EMSY represses transcription of antimetastatic microRNA miR-31.
abstract: Amplification of the EMSY gene in sporadic breast and ovarian cancers is a poor prognostic indicator. Although EMSY has been linked to transcriptional silencing, its mechanism of action is unknown. Here, we report that EMSY acts as an oncogene, causing the transformation of cells in vitro and potentiating tumor formation and metastatic features in vivo. We identify an inverse correlation between EMSY amplification and miR-31 expression, an antimetastatic microRNA, in the METABRIC cohort of human breast samples. Re-expression of miR-31 profoundly reduced cell migration, invasion, and colony-formation abilities of cells overexpressing EMSY or haboring EMSY amplification. We show that EMSY is recruited to the miR-31 promoter by the DNA binding factor ETS-1, and it represses miR-31 transcription by delivering the H3K4me3 demethylase JARID1b/PLU-1/KDM5B. Altogether, these results suggest a pathway underlying the role of EMSY in breast cancer and uncover potential diagnostic and therapeutic targets in sporadic breast cancer.
authors.affiliation: Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Viré
authors.affiliation: Department of Oncology and Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, CB2 0RE, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Curtis
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona 08907, Spain.
authors.forename: Veronica
authors.initials: V
authors.lastname: Davalos
authors.affiliation: Department of Oncology and Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, CB2 0RE, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Git
authors.affiliation: Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
authors.forename: Samuel
authors.initials: S
authors.lastname: Robson
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona 08907, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Department of Pathological Anatomy, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona 08907, Spain.
authors.forename: August
authors.initials: A
authors.lastname: Vidal
authors.forename: Isaia
authors.initials: I
authors.lastname: Barbieri
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency, 675 West 10(th) Avenue, V5Z 1L3 Vancouver, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona 08907, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Department of Oncology and Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, CB2 0RE, UK; Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital, NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK; Cambridge Experimental Cancer Medicine Centre (ECMC), Cambridge CB2 0RE, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK. Electronic address: t.kouzarides@gurdon.cam.ac.uk.
authors.forename: Tony
authors.initials: T
authors.lastname: Kouzarides
mesh_terms: D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism*; D002465:Cell Movement; D015331:Cohort Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D009857:Oncogenes / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: C480344:EMSY protein, human; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins