title: EglN2 contributes to triple negative breast tumorigenesis by functioning as a substrate for the FBW7 tumor suppressor.
abstract: 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.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Takada
authors.affiliation: Department of General Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhuang
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inuzuka
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Giada
authors.initials: G
authors.lastname: Zurlo
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Jinfang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.|Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004795:Enzyme Stability; D000073979:F-Box-WD Repeat-Containing Protein 7 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C513272:Fbxw7 protein, mouse; D025521:Tumor Suppressor Proteins; C522721:PHD1 protein, mouse; D011393:Procollagen-Proline Dioxygenase; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta
keywords: EglN2; FBW7; triple negative breast cancer