Opposing roles of PIK3CA gene alterations to EZH2 signaling in non-muscle invasive bladder cancer
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Cristina Segovia1,2,3,*, Mónica Martínez-Fernández1,2,3,*, Marta Dueñas1,2,3,*, Carolina Rubio2,3, Fernando F. López-Calderón2, Clotilde Costa1,4, Cristina Saiz-Ladera1,5, María Fernández-Grajera1, José Duarte2,3, Huberto García Muñoz6, Federico de la Rosa2,3, Felipe Villacampa2,3, Daniel Castellano2,3, Jesús M. Paramio1,2,3
1Unidad de Oncología Molecular, CIEMAT (ed70A), Madrid, Spain
2Grupo de Oncología celular y Molecular, Hospital Universitario 12 de Octubre, Madrid, Spain
3Centro de Investigación Biomédica en Red de Cáncer (CIBER ONC), Spain
4Unidad Mixta Roche-CHUS, Hospital Universitario de Santiago de Compostela, Travesía de Choupana, s/n, Santiago de Compostela, A Coruña, Spain
5Departamento de Bioquímica y Biología Molecular I, Facultad de Biología, Universidad Complutense, Madrid, Spain
6Servicio de Anatomía Patológica, Hospital Universitario 12 de Octubre, Instituto de Investigación 12 de Octubre i+12, UCM, Av Cordoba s/n, Madrid, Spain
*These authors have contributed equally to this work
Jesus M. Paramio, email: [email protected]
Keywords: bladder cancer, PIK3CA, genomics, Ezh2, recurrence progression
Received: July 20, 2016 Accepted: December 12, 2016 Published: January 02, 2017
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.
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