Regulation of XIAP Turnover Reveals a Role for USP11 in Promotion of Tumorigenesis.
Regulation of XIAP Turnover Reveals a Role for USP11 in Promotion of Tumorigenesis.
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DOI：
10.1016/j.ebiom.2016.12.014
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发表时间：
2017-02
期刊：
影响因子：
11.1
通讯作者：
Wan Y
中科院分区：
文献类型：
--
作者：
Zhou Z;Luo A;Shrivastava I;He M;Huang Y;Bahar I;Liu Z;Wan Y
去泛素酶 (DUB) 的新兴调节作用与各种基本过程和发病机制有关。为了确定 DUB 在介导肿瘤发生中发挥的关键作用，我们基于乳腺细胞转化测定对 67 种人类 DUB 进行了无偏见筛选。这导致 USP11 被确定为乳腺肿瘤发生和进展的关键决定因素。使用蛋白质复合物纯化与质谱联用的方法，我们进一步确定 XIAP 是 USP11 的目标。我们证明，虽然 XIAP 的消耗减弱了细胞转化，但 USP11 的升高通过稳定 XIAP 显着促进肿瘤集落形成。分子建模结合诱变分析进一步揭示 XIAP BIR2 结构域上的 Leu207 促进其与 USP11 的相互作用。由于 USP11 去泛素化，XIAP 变得稳定，从而抑制细胞失巢凋亡和细胞凋亡，进而促进肿瘤发生。 Finally, immunohistochemical staining revealed that aberrant accumulation of USP11 correlates with elevated levels of XIAP in breast cancer tissues.因此，我们认为异常的 USP11 通过稳定 XIAP 促进肿瘤的发生和进展。通过去泛素酶库的无偏筛选，鉴定 USP11 作为促进肿瘤发生的关键参与者。使用 TAP-蛋白质复合物纯化结合质谱法鉴定 XIAP 作为 USP11 的底物。 USP11 稳定 XIAP 会抑制失巢凋亡和细胞凋亡，进而促进肿瘤细胞存活。靶向泛素-蛋白酶体途径成为开发抗癌治疗的新兴策略。去泛素酶在对抗泛素化和调节肿瘤发生方面的影响最近引起了我们的关注。为了系统地评估人类基因组中的去泛素酶在调节乳腺肿瘤发生中的作用，我们对去泛素酶库进行了无偏筛选，并检查了单个去泛素酶在使正常乳腺细胞易变成癌细胞的过程中的作用。我们的努力导致 USP11 被鉴定为促进乳腺肿瘤形成的关键参与者。我们的分子表征进一步揭示了 USP11 对 XIAP 的稳定作用导致抑制癌细胞死亡，从而促进肿瘤发生。
The emerging regulatory role of deubiquitinases (DUBs) has been implicated in various fundamental processes and pathogenesis. To determine the pivotal role that DUBs play in mediating tumorigenesis, we have performed a non-biased screen of 67 human DUBs based on a mammary cell transformation assay. This led to the identification of USP11 as a critical determinant of mammary tumor initiation and progression. Using an approach of protein complex purification coupled with mass spectrometry, we further identified XIAP to be a target for USP11. We demonstrated that, while depletion of XIAP attenuates cell transformation, elevated USP11 significantly promotes the tumor colony formation through stabilization of XIAP. Molecular modeling coupled with mutagenesis analyses further revealed that Leu207 on the BIR2 domain of XIAP facilitates its interaction with USP11. Stabilization of XIAP due to its deubiquitylation by USP11 leads to the inhibition of cell anoikis and apoptosis, which in turn promotes tumorigenesis. Finally, immunohistochemical staining revealed that aberrant accumulation of USP11 correlates with elevated levels of XIAP in breast cancer tissues. We therefore propose that aberrant USP11, via stabilization of XIAP, promotes tumor initiation and progression. Identification of USP11 as a pivotal player in promoting tumorigenesis via a non-biased screening of deubiquitinase library. Identification of XIAP as a substrate for USP11 using a TAP-protein complex purification coupled with mass spectrometry. Stabilization of XIAP by USP11 leads to inhibition of anoikis and apoptosis that in turn promotes tumor cell survival. Targeting ubiquitin-proteasome pathway becomes an emerging strategy to develop anti-cancer treatment. The impact of deubiquitinase in counteracting ubiquitylation and regulating tumorigenesis has recently drawn our attention. To systematically evaluate the role of deubiquitinases in human genome in regulating mammary tumorigenesis, we have conducted a non-biased screening of deubiquitinases library with examination of individual deubiquitinase in predisposing normal mammary gland cell into cancer cell. Our endeavor leads to identification of USP11 as a pivotal player that promotes mammary tumor formation. Our molecular characterization has further revealed that stabilization of XIAP by USP11 results in the inhibition of cancer cell death thereby promoting tumorigenesis.