title: MYC is activated by USP2a-mediated modulation of microRNAs in prostate cancer.
abstract: Ubiquitin-specific protease 2a (USP2a) is overexpressed in almost half of human prostate cancers and c-Myc is amplified in one third of these tumor types. Transgenic MYC expression drives invasive adenocarcinomas in the murine prostate. We show that overexpression of USP2a downregulates a set of microRNAs that collectively increase MYC levels by MDM2 deubiquitination and subsequent p53 inactivation. By establishing MYC as a target of miR-34b/c, we demonstrate that this cluster functions as a tumor suppressor in prostate cancer cells. We identify a distinct mRNA signature that is enriched for MYC-regulated transcripts and transcription factor binding sites in USP2a overexpressing prostate cancer cells. We demonstrate that these genes are associated with an invasive phenotype in human prostate cancer and that the proliferative and invasive properties of USP2a overexpressing cells are MYC-dependent. These results highlight an unrecognized mechanism of MYC regulation in prostate cancer and suggest alternative therapeutic strategies in targeting MYC.
  
  
  CONCLUSIONS
  The deubiquitinating enzyme USP2a has previously been shown to be oncogenic, overexpressed in almost half of human prostate adenocarcinomas, and prolongs the half-life of targets such as fatty acid synthase, MDM2, and cyclin D1. Here, we highlight a new mechanism by which USP2a enhances MYC levels through the modulation of specific subsets of microRNAs in prostate cancer, suggesting alternative therapeutic strategies for targeting MYC.
authors.affiliation: Translational Oncogenomics Unit, Regina Elena Cancer Institute, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Benassi
authors.forename: Richard
authors.initials: R
authors.lastname: Flavin
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.forename: Silvio
authors.initials: S
authors.lastname: Zanata
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Pan
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chowdhury
authors.forename: Marina
authors.initials: M
authors.lastname: Marani
authors.forename: Sabrina
authors.initials: S
authors.lastname: Strano
authors.forename: Paola
authors.initials: P
authors.lastname: Muti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Blandino
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
mesh_terms: D048708:Cell Growth Processes / Q000502:physiology; D015536:Down-Regulation; D010450:Endopeptidases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D043222:Ubiquitin Thiolesterase
chemical_list: C522425:MIRN34 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D010450:Endopeptidases; C108665:USP2 protein, human; D043222:Ubiquitin Thiolesterase