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

• Published in: Oncotarget Vol. 7; no. 16; pp. 22791 - 22806
• Main Authors: Kumar, Parameet, Sharad, Shashwat, Petrovics, Gyorgy, Mohamed, Ahmed, Dobi, Albert, Sreenath, Taduru L, Srivastava, Shiv, Biswas, Roopa
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 19-04-2016
• Subjects: Cell Line, Tumor; Gene Expression Regulation, Neoplastic - physiology; Humans; Male; MicroRNAs - genetics; MicroRNAs - metabolism; Neoplasm Invasiveness - genetics; Phenotype; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Research Paper; Sirtuin 1 - biosynthesis; Transcriptional Regulator ERG - genetics; miR-449a; microRNA; prostate cancer; ERG; SIRT1
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.8061

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.