title: Opposing roles of PIK3CA gene alterations to EZH2 signaling in non-muscle invasive bladder cancer.
abstract: The high rates of tumor recurrence and progression represent a major clinical problem in non-muscle invasive bladder cancer. Previous data showed that EZH2-dependent signaling mediates these processes, whereas the frequent alterations of PIK3CA gene (copy gains and mutations) are predictive of reduced recurrence. Here we show, using clinical samples and bladder cancer cell lines, a functional interaction between EZH2- and PIK3CA-dependent signaling pathways. PIK3CA alterations mediated, on the one hand, the increased expression of two miRNAs, miR-101 and miR-138, which posttranscriptionally downregulate EZH2 expression. On the other hand, PIK3CA alterations facilitate the activation of Akt which phosphorylates EZH2 on Ser21, precluding the trimethylation of histone H3 in K27. Remarkably the increased expression of miR101 or miR138 and the expression of Ser21-phosphorylated EZH2 are good prognostic factors regarding non-muscle invasive bladder cancer recurrence and progression. Collectively, this study provides molecular evidences indicating that the gene expression rewiring occurring in primary bladder tumors, associated with increased EZH2 expression and activity and mediating the increased recurrence and progression risk, are prevented by PIK3CA-dependent signaling. This molecular process may have deep implications in the management of bladder cancer patients and in the design of novel molecularly targeted therapeutic approaches.
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), Madrid, Spain.|Grupo de Oncología celular y Molecular, Hospital Universitario 12 de Octubre, Madrid, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBER ONC), Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Segovia
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), Madrid, Spain.|Grupo de Oncología celular y Molecular, Hospital Universitario 12 de Octubre, Madrid, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBER ONC), Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Martínez-Fernández
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), Madrid, Spain.|Grupo de Oncología celular y Molecular, Hospital Universitario 12 de Octubre, Madrid, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBER ONC), Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Dueñas
authors.affiliation: Grupo de Oncología celular y Molecular, Hospital Universitario 12 de Octubre, Madrid, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBER ONC), Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Rubio
authors.affiliation: Grupo de Oncología celular y Molecular, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Fernando F
authors.initials: FF
authors.lastname: López-Calderón
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), Madrid, Spain.|Unidad Mixta Roche-CHUS, Hospital Universitario de Santiago de Compostela, Travesía de Choupana, s/n, Santiago de Compostela, A Coruña, Spain.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Costa
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), Madrid, Spain.|Departamento de Bioquímica y Biología Molecular I, Facultad de Biología, Universidad Complutense, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Saiz-Ladera
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Fernández-Grajera
authors.affiliation: Grupo de Oncología celular y Molecular, Hospital Universitario 12 de Octubre, Madrid, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBER ONC), Spain.
authors.forename: José
authors.initials: J
authors.lastname: Duarte
authors.affiliation: Servicio de Anatomía Patológica, Hospital Universitario 12 de Octubre, Instituto de Investigación 12 de Octubre i+12, UCM, Av Cordoba s/n, Madrid, Spain.
authors.forename: Huberto García
authors.initials: HG
authors.lastname: Muñoz
authors.affiliation: Grupo de Oncología celular y Molecular, Hospital Universitario 12 de Octubre, Madrid, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBER ONC), Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: de la Rosa
authors.affiliation: Grupo de Oncología celular y Molecular, Hospital Universitario 12 de Octubre, Madrid, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBER ONC), Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Villacampa
authors.affiliation: Grupo de Oncología celular y Molecular, Hospital Universitario 12 de Octubre, Madrid, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBER ONC), Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Castellano
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), Madrid, Spain.|Grupo de Oncología celular y Molecular, Hospital Universitario 12 de Octubre, Madrid, Spain.|Centro de Investigación Biomédica en Red de Cáncer (CIBER ONC), Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Paramio
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008745:Methylation; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones; C534072:MIRN101 microRNA, human; C546110:MIRN138 microRNA, human; D035683:MicroRNAs; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: Ezh2; PIK3CA; bladder cancer; genomics; recurrence progression