Format

Send to

Choose Destination
Cancer Discov. 2012 Mar;2(3):236-47. doi: 10.1158/2159-8290.CD-11-0219. Epub 2012 Jan 5.

MYC is activated by USP2a-mediated modulation of microRNAs in prostate cancer.

Author information

1
Translational Oncogenomics Unit, Regina Elena Cancer Institute, Rome, Italy.

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.

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.

Comment in

PMID:
22585994
PMCID:
PMC3523361
DOI:
10.1158/2159-8290.CD-11-0219
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center