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Cancer Discov 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 Discov
Volume2
Issue3
Pages236-47
Date Published2012 Mar
ISSN2159-8290
KeywordsCell Growth Processes, Down-Regulation, Endopeptidases, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Genes, myc, Humans, Male, MicroRNAs, Neoplasm Invasiveness, Prostatic Neoplasms, Proto-Oncogene Proteins c-mdm2, Proto-Oncogene Proteins c-myc, RNA, Messenger, Tumor Suppressor Protein p53
Abstract

UNLABELLED: 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.

SIGNIFICANCE: 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.

URLhttp://cancerdiscovery.aacrjournals.org/cgi/pmidlookup?view=long&pmid=22585994
DOI10.1158/2159-8290.CD-11-0219
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22585994?dopt=Abstract

Alternate JournalCancer Discov
PubMed ID22585994
PubMed Central IDPMC3523361
Grant ListP01CA89021 / CA / NCI NIH HHS / United States
P50 CA090381 / CA / NCI NIH HHS / United States
P30CA006973 / CA / NCI NIH HHS / United States
P30 CA006973 / CA / NCI NIH HHS / United States
R01 CA131945-05 / CA / NCI NIH HHS / United States
R01CA131945 / CA / NCI NIH HHS / United States
R01 CA131945 / CA / NCI NIH HHS / United States
P50CA90381 / CA / NCI NIH HHS / United States
R01 CA142698 / CA / NCI NIH HHS / United States
P01 CA089021 / CA / NCI NIH HHS / United States