Oncotarget

Research Papers:

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

Parameet Kumar, Shashwat Sharad, Gyorgy Petrovics, Ahmed Mohamed, Albert Dobi, Taduru L. Sreenath, Shiv Srivastava and Roopa Biswas _

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Oncotarget. 2016; 7:22791-22806. https://doi.org/10.18632/oncotarget.8061

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Abstract

Parameet Kumar1, Shashwat Sharad2, Gyorgy Petrovics2, Ahmed Mohamed2, Albert Dobi2, Taduru L. Sreenath2, Shiv Srivastava2, Roopa Biswas1

1Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814 USA

2Department 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: [email protected]

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.


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