c-Myc is activated via USP2a-mediated modulation of microRNAs in prostate cancer
Cette étude met en évidence un mécanisme impliquant l'enzyme USP2a dans la régulation du gène c-Myc au sein des cellules de cancer de la prostate
Ubiquitin-Specific Protease 2a (USP2a) is over-expressed in almost half of human prostate cancers and c-Myc is amplified in a third of these tumour types. As a transgene c-Myc results in invasive adenocarcinomas in the murine prostate. We show that over-expression of USP2a, down-regulates a set of microRNAs (miRNAs) which collectively increase c-Myc, via Mdm2 de-ubiquitination and subsequent p53 inactivation. By establishing c-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, which is enriched for c-Myc-regulated transcripts and transcription factor binding sites in USP2a over-expressing 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 over-expressing cells are c-Myc-dependent. These results highlight an unrecognized mechanism of c-Myc regulation in prostate cancer and suggest alternative therapeutic strategies in targeting Myc.
Cancer Discovery 2012