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Cancer discovery DOI:10.1158/2159-8290.CD-11-0219

MYC Is Activated by USP2a-Mediated Modulation of MicroRNAs in Prostate Cancer.

Publication TypeJournal Article
Year of Publication2012
AuthorsBenassi, B, Flavin, R, Marchionni, L, Zanata, S, Pan, Y, Chowdhury, D, Marani, M, Strano, S, Muti, P, Blandino, G, Loda, M
JournalCancer discovery
Date Published2012/03/01

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.