Loss of miR-449a in ERG-associated prostate cancer promotes the invasive phenotype by inducing SIRT1

// Parameet Kumar 1 , Shashwat Sharad 2 , Gyorgy Petrovics 2 , Ahmed Mohamed 2 , Albert Dobi 2 , Taduru L. Sreenath 2 , Shiv Srivastava 2 , Roopa Biswas 1 1 Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814 USA 2 Department of Surgery and Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814 USA Correspondence to: Roopa Biswas, e-mail: roopa.biswas@usuhs.edu Keywords: microRNA, miR-449a, SIRT1, ERG, prostate cancer Received: January 11, 2016      Accepted: February 25, 2016      Published: March 14, 2016 ABSTRACT Epigenetic regulation by SIRT1, a multifaceted NAD + -dependent protein deacetylase, is one of the most common factors modulating cellular processes in a broad range of diseases, including prostate cancer (CaP). SIRT1 is over-expressed in CaP cells, however the associated mechanism is not well understood. To identify whether specific microRNAs might mediate this linkage, we have screened a miRNA library for differential expression in ERG-associated CaP tissues. Of 20 differentially and significantly expressed miRNAs that distinguish ERG-positive tumors from ERG-negative tumors, we find miR-449a is highly suppressed in ERG-positive tumors. We establish that SIRT1 is a direct target of miR-449a and is also induced by ERG in ERG-associated CaP. Our data suggest that attenuation of miR-449a promotes the invasive phenotype of the ERG-positive CaP in part by inducing the expression of SIRT1 in prostate cancer cells. Furthermore, we also find that suppression of SIRT1 results in a significant reduction in ERG expression in ERG-positive CaP cells, indicating a feed-back regulatory loop associated with ERG, miR-449a and SIRT1. We also report that ERG suppresses p53 acetylation perhaps through miR-449a-SIRT1 axis in CaP cells. Our findings provide new insight into the function of miRNAs in regulating ERG-associated CaP. Thus, miR-449a activation or SIRT1 suppression may represent new therapeutic opportunity for ERG-associated CaP.