Molecular mechanism of the TP53-MDM2-AR-AKT signalling network regulation by USP12
Molecular mechanism of the TP53-MDM2-AR-AKT signalling network regulation by USP12
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DOI：
10.1038/s41388-018-0283-3
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发表时间：
2018-08-23
期刊：
影响因子：
8
通讯作者：
Robson, Craig N.
中科院分区：
文献类型：
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作者：
McClurg, Urszula L.;Chit, Nay C. T. H.;Robson, Craig N.
TP53-MDM2-AR-AKT信号网络在前列腺癌的发生和进展中发挥着关键作用。然而，调节该信号网络的分子机制尚未完全确定。通过转录组分析、变性免疫沉淀和免疫病理学，我们证明前列腺癌中 TP53-MDM2-AR-AKT 串扰受到去泛素化酶 USP12 的调节。我们的研究结果解释了为什么 USP12 是位于扩增超级增强子附近的 12 个最常过度表达的癌症相关基因之一。我们发现 USP12 使 MDM2 和 AR 去泛素化，进而控制前列腺癌中 TP53 肿瘤抑制基因和 AR 癌基因的水平。因此，USP12 水平不仅可以预测癌症的发展，还可以预测患者的治疗耐药性、复发和生存。因此，我们的研究结果表明，USP12 可以作为目前无法治愈的去势抵抗性前列腺癌的有前景的治疗靶点。
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.