Nguyen Hung Thanh, Kugler Jan-Michael, Loya Anand C, Cohen Stephen M
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
Department of Pathology, Rigshospitalet, Copenhagen, Denmark.
Oncotarget. 2017 Jul 18;8(38):64095-64105. doi: 10.18632/oncotarget.19322. eCollection 2017 Sep 8.
The Hippo pathway, which acts to repress the activity of YAP and TAZ trancriptional co-activators, serve as a barrier for oncogenic transformation. Unlike other oncoproteins, YAP and TAZ are rarely activated by mutations or amplified in cancer. However, elevated YAP/TAZ activity is frequently observed in cancer and often correlates with worse survival. The activity and stability of Hippo pathway components, including YAP/TAZ, AMOT and LATS1/2, are regulated by ubiquitin-mediated protein degradation. Aberrant expression of ubiquitin ligase complexes that regulate the turnover of Hippo components and deubiquitylating enzymes that counteract these ubiquitin ligases have been implicated in human cancer. Here we identify the USP21 deubiquitylating enzyme as a novel regulator of Hippo pathway activity. We provide evidence that USP21 regulates YAP/TAZ activity by controlling the stability of MARK kinases, which promote Hippo signaling. Low expression of USP21 in early stage renal clear cell carcinoma suggests that USP21 may be a useful biomarker.
河马通路可抑制YAP和TAZ转录共激活因子的活性，是致癌转化的一道屏障。与其他癌蛋白不同，YAP和TAZ在癌症中很少因突变而被激活或扩增。然而，在癌症中经常观察到YAP/TAZ活性升高，且往往与较差的生存率相关。包括YAP/TAZ、AMOT和LATS1/2在内的河马通路组分的活性和稳定性受泛素介导的蛋白质降解调控。调节河马组分周转的泛素连接酶复合物以及对抗这些泛素连接酶的去泛素化酶的异常表达与人类癌症有关。在此，我们鉴定出USP21去泛素化酶是河马通路活性的一种新型调节因子。我们提供的证据表明，USP21通过控制促进河马信号传导的MARK激酶的稳定性来调节YAP/TAZ活性。USP21在早期肾透明细胞癌中的低表达表明它可能是一种有用的生物标志物。
