Genomic and Functional Analysis of the E3 Ligase PARK2 in Glioma.
Genomic and Functional Analysis of the E3 Ligase PARK2 in Glioma.
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胶质瘤中 E3 连接酶 PARK2 的基因组和功能分析。
DOI：
10.1158/0008-5472.can-14-1433
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发表时间：
2015-05-01
期刊：
影响因子：
11.2
通讯作者：
Koeffler HP
中科院分区：
文献类型：
--
作者：
Lin DC;Xu L;Chen Y;Yan H;Hazawa M;Doan N;Said JW;Ding LW;Liu LZ;Yang H;Yu S;Kahn M;Yin D;Koeffler HP
PARK2(Parkin)是一种E3泛素连接酶，其功能障碍与帕金森病和人类恶性肿瘤的进展有关，其在癌症中的作用仍有待探讨。在这项研究中，我们报告了PARK2在人脑胶质瘤中经常缺失和低表达，低表达与预后不良有关。PARK2的修复在体外和体内都显著抑制了胶质瘤细胞的生长，而PARK2的缺失促进了细胞的增殖。PARK2通过下调细胞内β-连环蛋白和表皮生长因子受体的水平来减弱Wnt和EGF刺激的通路。值得注意的是，PARK2与β-连环蛋白和表皮生长因子受体在物理上都相互作用。我们进一步发现，PARK2以E3连接酶活性依赖的方式促进这两种蛋白的泛素化。最后，受这些新发现的PARK2的肿瘤抑制功能的启发，我们测试并证明了针对WNT-β-连环蛋白和EGFR-AKT通路的小分子抑制剂的组合协同地损害了胶质瘤细胞的活力。总之，我们的发现揭示了PARK2与癌症相关的新功能，并为治疗胶质瘤提供了一种潜在的治疗方法。
PARK2 (PARKIN) is an E3 ubiquitin ligase whose dysfunction has been associated with the progression of Parkinsonism and human malignancies, and its role in cancer remains to be explored. In this study, we report that PARK2 is frequently deleted and underexpressed in human glioma, and low PARK2 expression is associated with poor survival. Restoration of PARK2 significantly inhibited glioma cell growth both in vitro and in vivo, whereas depletion of PARK2 promoted cell proliferation. PARK2 attenuated both Wnt- and EGF-stimulated pathways through downregulating the intracellular level of β-catenin and EGFR. Notably, PARK2 physically interacted with both β-catenin and EGFR. We further found that PARK2 promoted the ubiquitination of these two proteins in an E3 ligase activity-dependent manner. Finally, inspired by these newly identified tumor-suppressive functions of PARK2, we tested and proved that combination of small-molecule inhibitors targeting both Wnt-β-catenin and EGFR-AKT pathways synergistically impaired glioma cell viability. Together, our findings uncover novel cancer-associated functions of PARK2 and provide a potential therapeutic approach to treat glioma.