EglN2 contributes to triple negative breast tumorigenesis by functioning as a substrate for the FBW7 tumor suppressor
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Mamoru Takada1,*, Ming Zhuang2,*, Hiroyuki Inuzuka3, Jing Zhang1, Giada Zurlo1, Jinfang Zhang3, Qing Zhang1,4
1Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
2Department of General Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
3Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
4Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
*These authors have contributed equally to this work
Qing Zhang, email: Qing_Zhang@med.unc.edu
Keywords: EglN2, triple negative breast cancer, FBW7
Received: September 01, 2016 Accepted: December 13, 2016 Published: December 27, 2016
EglN2 contributes to ERα-positive breast tumorigenesis by acting as an estrogen-inducible gene. However, the detailed molecular mechanism(s) underlying the post-transcriptional regulation of EglN2 and its potential role in Triple Negative Breast Cancer (TNBC) remains largely unclear. By using C3Tag transgenic mice and tumor-derived C3Tag cell line, here we report that EglN2 contributes to TNBC tumor progression and genetic knockout of EglN2 improves C3Tag mice survival from tumor progression. Mechanistically, we further show that FBW7, an E3 ligase complex component that is frequently downregulated in TNBC, negatively regulates EglN2 protein stability. As such, depletion of FBW7 in breast cell lines leads to upregulation of EglN2 and other canonical FBW7 substrates. Conversely, FBW7 overexpression leads to EglN2 downregulation in a GSK3β-dependent manner. Furthermore, we identified some potential serine or threonine residues on the C-terminal of EglN2 that may mediate its binding and potential regulation by FBW7. Together, our study reveals that EglN2 might act as an FBW7 ubiquitin ligase substrate contributing to TNBC.
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