دورية أكاديمية
أعرض في EDS

Contribution of synergism between PHF8 and HER2 signalling to breast cancer development and drug resistance.

التفاصيل البيبلوغرافية
العنوان: Contribution of synergism between PHF8 and HER2 signalling to breast cancer development and drug resistance.
المؤلفون: Liu Q; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA., Borcherding NC; Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA., Shao P; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA., Maina PK; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Albert Einstein College of Medicine, Bronx, NY, 10461, USA., Zhang W; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, 32610-0275, USA., Qi HH; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA. Electronic address: hank-qi@uiowa.edu.
المصدر: EBioMedicine [EBioMedicine] 2020 Jan; Vol. 51, pp. 102612. Date of Electronic Publication: 2020 Jan 07.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier B.V Country of Publication: Netherlands NLM ID: 101647039 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2352-3964 (Electronic) Linking ISSN: 23523964 NLM ISO Abbreviation: EBioMedicine Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Amsterdam] : Elsevier B.V., [2014]-
مواضيع طبية MeSH: Drug Resistance, Neoplasm*/genetics , Signal Transduction*, Breast Neoplasms/*metabolism , Breast Neoplasms/*pathology , Histone Demethylases/*metabolism , Receptor, ErbB-2/*metabolism , Transcription Factors/*metabolism, Animals ; Breast Neoplasms/genetics ; Carcinogenesis/genetics ; Carcinogenesis/pathology ; Cell Line, Tumor ; Female ; Gene Expression Regulation, Neoplastic ; HEK293 Cells ; Humans ; Interleukin-6/metabolism ; Mice, Knockout ; Trans-Activators/metabolism ; Up-Regulation/genetics
مستخلص: Background: HER2 plays a critical role in tumourigenesis and is associated with poor prognosis of patients with HER2-positive breast cancers. Although anti-HER2 drugs are beneficial for treating breast cancer, de novo, or acquired resistance often develops. Epigenetic factors are increasingly targeted for therapy; however, such mechanisms that interact with HER2 signalling are poorly understood.
Methods: RNA sequencing was performed to identify PHF8 targets downstream of HER2 signalling. CHIP-qPCR were used to investigate how PHF8 regulates HER2 transcription. ELISA determined cytokine secretion. Cell-based assay revealed a feed forward loop in HER2 signalling and then evaluated in vivo.
Findings: We report the synergistic interplay between histone demethylase PHF8 and HER2 signalling. Specifically, PHF8 levels were elevated in HER2-positive breast cancers and upregulated by HER2. PHF8 functioned as a coactivator that regulated the expression of HER2, markers of the HER2-driven epithelial-to-mesenchymal transition and cytokines. The HER2-PHF8-IL-6 regulatory axis was active in cell lines and in newly established MMTV-Her2/MMTV-Cre/Phf8 fl ° x/fl ° x mouse models, which revealed the oncogenic function of Phf8 in breast cancer for the first time. Further, the PHF8-IL-6 axis contributed to the resistance to trastuzumab in vitro and may play a critical role in the infiltration of T cells in HER2-driven breast cancers.
Interpretation: These findings provided informative mechanistic insight into the potential application of PHF8 inhibitors to overcome resistance to anti-HER2 therapies.
Funding: This work was supported by Carver Trust Young Investigator Award (01-224 to H.H.Q); and a Breast Cancer Research Award (to H.H.Q.).
Competing Interests: Declaration of competing interests The authors claim no conflict of interest.
(Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
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معلومات مُعتمدة: F30 CA206255 United States CA NCI NIH HHS; P30 CA086862 United States CA NCI NIH HHS; R01 CA200673 United States CA NCI NIH HHS; T32 GM007337 United States GM NIGMS NIH HHS; R01 CA203834 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: Breast cancer; Drug resistance; HER2; IL-6; PHF8
المشرفين على المادة: 0 (Interleukin-6)
0 (Trans-Activators)
0 (Transcription Factors)
EC 1.14.11.- (Histone Demethylases)
EC 1.14.11.- (PHF8 protein, human)
EC 2.7.10.1 (ERBB2 protein, human)
EC 2.7.10.1 (Receptor, ErbB-2)
تواريخ الأحداث: Date Created: 20200111 Date Completed: 20200930 Latest Revision: 20231113
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC7000350
DOI: 10.1016/j.ebiom.2019.102612
PMID: 31923801
قاعدة البيانات: MEDLINE
الوصف
تدمد:2352-3964
DOI:10.1016/j.ebiom.2019.102612