EglN2 contributes to triple negative breast tumorigenesis by functioning as a substrate for the FBW7 tumor suppressor.
EglN2 contributes to triple negative breast tumorigenesis by functioning as a substrate for the FBW7 tumor suppressor.
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DOI：
10.18632/oncotarget.14290
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发表时间：
2017-01-24
期刊：
影响因子：
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通讯作者：
Zhang Q
中科院分区：
文献类型：
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作者：
Takada M;Zhuang M;Inuzuka H;Zhang J;Zurlo G;Zhang J;Zhang Q
EglN 2作为雌激素诱导基因参与ERα阳性乳腺肿瘤的发生。然而，EglN 2的转录后调节的详细分子机制及其在三阴性乳腺癌（TNBC）中的潜在作用在很大程度上仍然不清楚。通过使用C3 Tag转基因小鼠和肿瘤衍生的C3 Tag细胞系，在这里，我们报告了EglN 2有助于TNBC肿瘤进展，并且EglN 2的基因敲除提高了C3 Tag小鼠的肿瘤进展存活率。从机制上讲，我们进一步表明FBW 7，一种在TNBC中经常下调的E3连接酶复合物组分，负调节EglN 2蛋白稳定性。因此，乳腺细胞系中FBW 7的消耗导致EglN 2和其他典型FBW 7底物的上调。相反，FBW 7过表达以GSK 3 β依赖性方式导致EglN 2下调。此外，我们确定了一些潜在的丝氨酸或苏氨酸残基上的C-末端的EglN 2，可能介导其结合和潜在的调节FBW 7。总之，我们的研究揭示了EglN 2可能充当促成TNBC的FBW 7泛素连接酶底物。
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.