title: Loss of miR-449a in ERG-associated prostate cancer promotes the invasive phenotype by inducing SIRT1.
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.
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814 USA.
authors.forename: Parameet
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Surgery and Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814 USA.
authors.forename: Shashwat
authors.initials: S
authors.lastname: Sharad
authors.affiliation: Department of Surgery and Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814 USA.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Petrovics
authors.affiliation: Department of Surgery and Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814 USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mohamed
authors.affiliation: Department of Surgery and Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814 USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Dobi
authors.affiliation: Department of Surgery and Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814 USA.
authors.forename: Taduru L
authors.initials: TL
authors.lastname: Sreenath
authors.affiliation: Department of Surgery and Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814 USA.
authors.forename: Shiv
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814 USA.
authors.forename: Roopa
authors.initials: R
authors.lastname: Biswas
mesh_terms: D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D056564:Sirtuin 1 / Q000096:biosynthesis*; D000071230:Transcriptional Regulator ERG / Q000235:genetics
chemical_list: C072312:ERG protein, human; C544530:MIRN449 microRNA, human; D035683:MicroRNAs; D000071230:Transcriptional Regulator ERG; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: ERG; SIRT1; miR-449a; microRNA; prostate cancer