Takada Mamoru, Zhuang Ming, Inuzuka Hiroyuki, Zhang Jing, Zurlo Giada, Zhang Jinfang, Zhang Qing
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Department of General Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Oncotarget. 2017 Jan 24;8(4):6787-6795. doi: 10.18632/oncotarget.14290.
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.
EglN2作为一种雌激素诱导基因，促进雌激素受体α阳性乳腺癌的发生。然而，EglN2转录后调控的详细分子机制及其在三阴性乳腺癌（TNBC）中的潜在作用仍不清楚。通过使用C3Tag转基因小鼠和肿瘤来源的C3Tag细胞系，我们在此报告EglN2促进TNBC肿瘤进展，EglN2基因敲除可提高C3Tag小鼠的肿瘤进展生存率。从机制上讲，我们进一步表明，FBW7是一种在TNBC中经常下调的E3连接酶复合物成分，它负向调节EglN2蛋白稳定性。因此，乳腺细胞系中FBW7的缺失导致EglN2和其他典型FBW7底物的上调。相反，FBW7的过表达以GSK3β依赖的方式导致EglN2下调。此外，我们在EglN2的C末端鉴定了一些潜在的丝氨酸或苏氨酸残基，它们可能介导其与FBW7的结合和潜在调控。总之，我们的研究表明EglN2可能作为一种FBW7泛素连接酶底物促进TNBC的发生。
