WBP2 promotes BTRC mRNA stability to drive migration and invasion in triple‐negative breast cancer via NF‐κB activation
WW‐domain‐binding protein 2 (WBP2) is an oncogene that drives breast carcinogenesis through regulating Wnt, estrogen receptor (ER), and Hippo signaling. Recent studies have identified neoteric modes of action of WBP2 other than its widely recognized function as a transcriptional coactivator. Here, w...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-01-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13048 |
| _version_ | 1819282343157825536 |
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| author | Yvonne Xinyi Lim Hexian Lin Tinghine Chu Yoon Pin Lim |
| author_facet | Yvonne Xinyi Lim Hexian Lin Tinghine Chu Yoon Pin Lim |
| author_sort | Yvonne Xinyi Lim |
| collection | DOAJ |
| description | WW‐domain‐binding protein 2 (WBP2) is an oncogene that drives breast carcinogenesis through regulating Wnt, estrogen receptor (ER), and Hippo signaling. Recent studies have identified neoteric modes of action of WBP2 other than its widely recognized function as a transcriptional coactivator. Here, we identified a previously unexplored role of WBP2 in inflammatory signaling in breast cancer via an integrated proteogenomic analysis of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA BRCA) dataset. WBP2 was shown to enhance the migration and invasion in triple‐negative breast cancer (TNBC) cells especially under tumor necrosis factor alpha (TNF‐α) stimulation. Molecularly, WBP2 potentiates TNF‐α‐induced nuclear factor kappa B (NF‐κB) transcriptional activity and nuclear localization through aggrandizing ubiquitin‐mediated proteasomal degradation of its upstream inhibitor, NF‐κB inhibitor alpha (NFKBIA; also known as IκBα). We further demonstrate that WBP2 induces mRNA stability of beta‐transducin repeat‐containing E3 ubiquitin protein ligase (BTRC), which targets IκBα for ubiquitination and degradation. Disruption of IκBα rescued the impaired migratory and invasive phenotypes in WBP2‐silenced cells, while loss of BTRC ameliorated WBP2‐driven migration and invasion. Clinically, the WBP2‐BTRC‐IκBα signaling axis correlates with poorer prognosis in breast cancer patients. Our findings reveal a pivotal mechanism of WBP2 in modulating BTRC‐IκBα‐NF‐κB pathway to promote TNBC aggressiveness. |
| first_indexed | 2024-12-24T01:14:04Z |
| format | Article |
| id | doaj.art-ad399c6154d54716b80011a847c44e9c |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-24T01:14:04Z |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-ad399c6154d54716b80011a847c44e9c2022-12-21T17:22:48ZengWileyMolecular Oncology1574-78911878-02612022-01-0116242244610.1002/1878-0261.13048WBP2 promotes BTRC mRNA stability to drive migration and invasion in triple‐negative breast cancer via NF‐κB activationYvonne Xinyi Lim0Hexian Lin1Tinghine Chu2Yoon Pin Lim3Integrative Sciences and Engineering Programme National University of Singapore SingaporeIntegrative Sciences and Engineering Programme National University of Singapore SingaporeIntegrative Sciences and Engineering Programme National University of Singapore SingaporeIntegrative Sciences and Engineering Programme National University of Singapore SingaporeWW‐domain‐binding protein 2 (WBP2) is an oncogene that drives breast carcinogenesis through regulating Wnt, estrogen receptor (ER), and Hippo signaling. Recent studies have identified neoteric modes of action of WBP2 other than its widely recognized function as a transcriptional coactivator. Here, we identified a previously unexplored role of WBP2 in inflammatory signaling in breast cancer via an integrated proteogenomic analysis of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA BRCA) dataset. WBP2 was shown to enhance the migration and invasion in triple‐negative breast cancer (TNBC) cells especially under tumor necrosis factor alpha (TNF‐α) stimulation. Molecularly, WBP2 potentiates TNF‐α‐induced nuclear factor kappa B (NF‐κB) transcriptional activity and nuclear localization through aggrandizing ubiquitin‐mediated proteasomal degradation of its upstream inhibitor, NF‐κB inhibitor alpha (NFKBIA; also known as IκBα). We further demonstrate that WBP2 induces mRNA stability of beta‐transducin repeat‐containing E3 ubiquitin protein ligase (BTRC), which targets IκBα for ubiquitination and degradation. Disruption of IκBα rescued the impaired migratory and invasive phenotypes in WBP2‐silenced cells, while loss of BTRC ameliorated WBP2‐driven migration and invasion. Clinically, the WBP2‐BTRC‐IκBα signaling axis correlates with poorer prognosis in breast cancer patients. Our findings reveal a pivotal mechanism of WBP2 in modulating BTRC‐IκBα‐NF‐κB pathway to promote TNBC aggressiveness.https://doi.org/10.1002/1878-0261.13048BTRCinvasionmigrationNFKBtriple‐negative breast cancerWBP2 |
| spellingShingle | Yvonne Xinyi Lim Hexian Lin Tinghine Chu Yoon Pin Lim WBP2 promotes BTRC mRNA stability to drive migration and invasion in triple‐negative breast cancer via NF‐κB activation Molecular Oncology BTRC invasion migration NFKB triple‐negative breast cancer WBP2 |
| title | WBP2 promotes BTRC mRNA stability to drive migration and invasion in triple‐negative breast cancer via NF‐κB activation |
| title_full | WBP2 promotes BTRC mRNA stability to drive migration and invasion in triple‐negative breast cancer via NF‐κB activation |
| title_fullStr | WBP2 promotes BTRC mRNA stability to drive migration and invasion in triple‐negative breast cancer via NF‐κB activation |
| title_full_unstemmed | WBP2 promotes BTRC mRNA stability to drive migration and invasion in triple‐negative breast cancer via NF‐κB activation |
| title_short | WBP2 promotes BTRC mRNA stability to drive migration and invasion in triple‐negative breast cancer via NF‐κB activation |
| title_sort | wbp2 promotes btrc mrna stability to drive migration and invasion in triple negative breast cancer via nf κb activation |
| topic | BTRC invasion migration NFKB triple‐negative breast cancer WBP2 |
| url | https://doi.org/10.1002/1878-0261.13048 |
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