EglN2 contributes to triple negative breast tumorigenesis by functioning as a substrate for the FBW7 tumor suppressor

Mamoru Takada, Ming Zhuang, Hiroyuki Inuzuka, Jing Zhang, Giada Zurlo, Jinfang Zhang, Qing Zhang

Research output: Contribution to journalArticle

Abstract

EglN2 contributes to ERα-positive breast tumorigenesis by acting as an estrogeninducible 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.

LanguageEnglish (US)
Pages6787-6795
Number of pages9
JournalOncotarget
Volume8
Issue number4
DOIs
StatePublished - 2017

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Triple Negative Breast Neoplasms
Carcinogenesis
Breast
Neoplasms
Down-Regulation
Cell Line
Ubiquitin-Protein Ligases
Protein Stability
Threonine
Ligases
Ubiquitin
Serine
Transgenic Mice
Up-Regulation
Breast Neoplasms
Genes

Keywords

  • EglN2
  • FBW7
  • Triple negative breast cancer

ASJC Scopus subject areas

  • Oncology

Cite this

EglN2 contributes to triple negative breast tumorigenesis by functioning as a substrate for the FBW7 tumor suppressor. / Takada, Mamoru; Zhuang, Ming; Inuzuka, Hiroyuki; Zhang, Jing; Zurlo, Giada; Zhang, Jinfang; Zhang, Qing.

In: Oncotarget, Vol. 8, No. 4, 2017, p. 6787-6795.

Research output: Contribution to journalArticle

Takada M, Zhuang M, Inuzuka H, Zhang J, Zurlo G, Zhang J et al. EglN2 contributes to triple negative breast tumorigenesis by functioning as a substrate for the FBW7 tumor suppressor. Oncotarget. 2017;8(4):6787-6795. Available from, DOI: 10.18632/oncotarget.14290
Takada, Mamoru ; Zhuang, Ming ; Inuzuka, Hiroyuki ; Zhang, Jing ; Zurlo, Giada ; Zhang, Jinfang ; Zhang, Qing. / EglN2 contributes to triple negative breast tumorigenesis by functioning as a substrate for the FBW7 tumor suppressor. In: Oncotarget. 2017 ; Vol. 8, No. 4. pp. 6787-6795
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