β-catenin negatively regulates expression of the prostaglandin transporter PGT in the normal intestinal epithelium and colorectal tumour cells: A role in the chemopreventive efficacy of aspirin

Background: Levels of the pro-tumorigenic prostaglandin PGE 2 are increased in colorectal cancer, previously attributed to increased synthesis through COX-2 upregulation and, more recently, to decreased catabolism. The functionally linked genes 15-prostaglandin dehydrogenase (15-PGDH) and the prostaglandin transporter PGT co-operate in prostaglandin degradation and are downregulated in colorectal cancer. We previously reported repression of 15-PGDH expression by the Wnt/β-catenin pathway, commonly deregulated during early colorectal neoplasia. Here we asked whether β-catenin also regulates PGT expression. Methods: The effect of β-catenin deletion in vivo was addressed by PGT immunostaining of β-catenin/lox-villin-cre-ERT2 mouse tissue. The effect of siRNA-mediated β-catenin knockdown and dnTCF4 induction in vitro was addressed by semi-quantitative and quantitative real-time RT-PCR and immunoblotting. Results: This study shows for the first time that deletion of β-catenin in murine intestinal epithelium in vivo upregulates PGT protein, especially in the crypt epithelium. Furthermore, β-catenin knockdown in vitro increases PGT expression in both colorectal adenoma-and carcinoma-derived cell lines, as does dnTCF4 induction in LS174T cells.Conclusions:These data suggest that β-catenin employs a two-pronged approach to inhibiting prostaglandin turnover during colorectal neoplasia by repressing PGT expression in addition to 15-PGDH. Furthermore, our data highlight a potential mechanism that may contribute to the non-selective NSAID aspirins chemopreventive efficacy. © 2012 Cancer Research UK All rights reserved

Molecular mechanism of the TP53-MDM2-AR-AKT signalling network regulation by USP12

The TP53-MDM2-AR-AKT signalling network plays a critical role in the development and progression of prostate cancer. However, the molecular mechanisms regulating this signalling network are not completely defined. By conducting transcriptome analysis, denaturing immunoprecipitations and immunopathology, we demonstrate that the TP53-MDM2-AR-AKT cross-talk is regulated by the deubiquitinating enzyme USP12 in prostate cancer. Our findings explain why USP12 is one of the 12 most commonly overexpressed cancer-associated genes located near an amplified super-enhancer. We find that USP12 deubiquitinates MDM2 and AR, which in turn controls the levels of the TP53 tumour suppressor and AR oncogene in prostate cancer. Consequently, USP12 levels are predictive not only of cancer development but also of patient’s therapy resistance, relapse and survival. Therefore, our findings suggest that USP12 could serve as a promising therapeutic target in currently incurable castrate-resistant prostate cancer