Journal article
Regulation of XIAP Turnover Reveals a Role for USP11 in Promotion of Tumorigenesis
EBioMedicine, Vol.15(C), pp.48-61
02/01/2017
DOI: 10.1016/j.ebiom.2016.12.014
PMCID: PMC5233825
PMID: 28040451
Abstract
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.
Details
- Title: Subtitle
- Regulation of XIAP Turnover Reveals a Role for USP11 in Promotion of Tumorigenesis
- Creators
- Zhuan Zhou - UPMC Hillman Cancer CenterAiping Luo - State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaIndira Shrivastava - University of PittsburghMingjing He - University of Pittsburgh School of MedicineYi Huang - UPMC Hillman Cancer CenterIvet Bahar - University of PittsburghZhihua Liu - Chinese Academy of Medical Sciences & Peking Union Medical CollegeYong Wan - UPMC Hillman Cancer Center
- Resource Type
- Journal article
- Publication Details
- EBioMedicine, Vol.15(C), pp.48-61
- Publisher
- Elsevier B.V
- DOI
- 10.1016/j.ebiom.2016.12.014
- PMID
- 28040451
- PMCID
- PMC5233825
- ISSN
- 2352-3964
- eISSN
- 2352-3964
- Language
- English
- Date published
- 02/01/2017
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984383898302771
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