A Polycomb-mir200 loop regulates clinical outcome in bladder cancer

// Mónica Martínez-Fernández 1, 2, * , Marta Dueñas 1, 2, * , Andrew Feber 3 , Cristina Segovia 1, 2 , Ramón García-Escudero 1, 2 , Carolina Rubio 1, 2 , Fernando F. López-Calderón 1, 2 , Claudio Díaz-García 1 , Felipe Villacampa 2, 4 , José Duarte 2, 4 , María J. Gómez-Rodriguez 2, 4 , Daniel Castellano 2, 4 , José L. Rodriguez-Peralto 5 , Federico de la Rosa 2, 4 , Stephan Beck 3 , Jesús M. Paramio 1, 2 1 Molecular Oncology Unit, CIEMAT (ed70A), 28040 Madrid, Spain 2 Universitary Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, 28041 Madrid, Spain 3 Medical Genomics, UCL Cancer Institute, University College London, London WC1E 6BT, UK 4 Uro-oncology Section, Universitary Hospital 12 de Octubre, 28041 Madrid, Spain 5 Anatomic Pathology Service, Universitary Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, 28041 Madrid, Spain * These authors have contributed equally to this work Correspondence to: Jesús M. Paramio, e-mail: jesusm.paramio@ciemat.es Keywords: miRNA, Polycomb, bladder cancer, recurrence, epigenetics Received: May 27, 2015      Accepted: October 04, 2015      Published: October 17, 2015 ABSTRACT Bladder cancer (BC) is a highly prevalent disease, ranking fifth in the most common cancers worldwide. Various miRNAs have recently emerged as potential prognostic biomarkers in cancer. The miR-200 family, which repressed the epithelial-to-mesenchymal transition (EMT), is repressed in multiple advanced cancers. However, its expression and function in BC is still poorly understood. Here we show that miR-200 family displays increased expression, probably due to the activation of specific oncogenic signaling pathways, and reduced promoter methylation, in BC compared to normal bladder samples. Furthermore, we show that the expression of these miRNAs is decreased in high grade and stage tumors, and the down-regulation is associated with patient’s poor clinical outcome. Our data indicate that the miR-200 family plays distinct roles in Non-Muscle (NMIBC) and Muscle-Invasive BC (MIBC). In MIBC, miR-200 expression post transcriptionally regulates EMT-promoting transcription factors ZEB1 and ZEB2, whereas suppresses BMI1 expression in NMIBC. Interestingly, we show that increased EZH2 and/or BMI1 expression repress the expression of miR-200 family members. Collectively, these findings support a model of BC progression through a coordinated action between the Polycomb Repression Complex (PRC) members repressing the miR-200 expression, which ultimately favors invasive BC development. Since pharmacological inhibition of EZH2 in BC cell lines lead to increased miR-200 expression, our findings may support new therapeutic strategies for BC clinical management.