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Histone deacetylase inhibitors dysregulate DNA repair proteins and antagonize metastasis-associated processes.
J Cancer Res Clin Oncol. 2020 Feb; 146(2):343-356.JC

Abstract

PURPOSE

We set out to determine whether clinically tested epigenetic drugs against class I histone deacetylases (HDACs) affect hallmarks of the metastatic process.

METHODS

We treated permanent and primary renal, lung, and breast cancer cells with the class I histone deacetylase inhibitors (HDACi) entinostat (MS-275) and valproic acid (VPA), the replicative stress inducer hydroxyurea (HU), the DNA-damaging agent cis-platinum (L-OHP), and the cytokine transforming growth factor-β (TGFβ). We used proteomics, quantitative PCR, immunoblot, single cell DNA damage assays, and flow cytometry to analyze cell fate after drug exposure.

RESULTS

We show that HDACi interfere with DNA repair protein expression and trigger DNA damage and apoptosis alone and in combination with established chemotherapeutics. Furthermore, HDACi disrupt the balance of cell adhesion protein expression and abrogate TGFβ-induced cellular plasticity of transformed cells.

CONCLUSION

HDACi suppress the epithelial-mesenchymal transition (EMT) and compromise the DNA integrity of cancer cells. These data encourage further testing of HDACi against tumor cells.

Authors+Show Affiliations

Department of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Straβe 67, 55131, Mainz, Germany. Department of Oncology, Luxembourg Institute of Health, 1445, Strassen, Luxembourg.Department of Otorhinolaryngology, University Medical Center Mainz, 55131, Mainz, Germany.Klinik Und Poliklinik für Innere Medizin II, Technical University of Munich, 81675, Munich, Germany. Hematology and Oncology, Charité-Universitätsmedizin Campus Benjamin Franklin, 12200, Berlin, Germany.Department of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Straβe 67, 55131, Mainz, Germany.Klinik Und Poliklinik für Innere Medizin II, Technical University of Munich, 81675, Munich, Germany.Department of Otorhinolaryngology, University Medical Center Mainz, 55131, Mainz, Germany.Clinic for Obstetrics and Women's Health, University Medical Center Mainz, 55131, Mainz, Germany. Department of Urology, University Medical Center Mainz, 55131, Mainz, Germany.Institute of Molecular Biology (IMB), 55128, Mainz, Germany.Department of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Straβe 67, 55131, Mainz, Germany. okraemer@uni-mainz.de.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31932908

Citation

Kiweler, Nicole, et al. "Histone Deacetylase Inhibitors Dysregulate DNA Repair Proteins and Antagonize Metastasis-associated Processes." Journal of Cancer Research and Clinical Oncology, vol. 146, no. 2, 2020, pp. 343-356.
Kiweler N, Wünsch D, Wirth M, et al. Histone deacetylase inhibitors dysregulate DNA repair proteins and antagonize metastasis-associated processes. J Cancer Res Clin Oncol. 2020;146(2):343-356.
Kiweler, N., Wünsch, D., Wirth, M., Mahendrarajah, N., Schneider, G., Stauber, R. H., Brenner, W., Butter, F., & Krämer, O. H. (2020). Histone deacetylase inhibitors dysregulate DNA repair proteins and antagonize metastasis-associated processes. Journal of Cancer Research and Clinical Oncology, 146(2), 343-356. https://doi.org/10.1007/s00432-019-03118-4
Kiweler N, et al. Histone Deacetylase Inhibitors Dysregulate DNA Repair Proteins and Antagonize Metastasis-associated Processes. J Cancer Res Clin Oncol. 2020;146(2):343-356. PubMed PMID: 31932908.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Histone deacetylase inhibitors dysregulate DNA repair proteins and antagonize metastasis-associated processes. AU - Kiweler,Nicole, AU - Wünsch,Désirée, AU - Wirth,Matthias, AU - Mahendrarajah,Nisintha, AU - Schneider,Günter, AU - Stauber,Roland H, AU - Brenner,Walburgis, AU - Butter,Falk, AU - Krämer,Oliver H, Y1 - 2020/01/13/ PY - 2019/11/09/received PY - 2019/12/19/accepted PY - 2020/1/15/pubmed PY - 2020/1/15/medline PY - 2020/1/15/entrez KW - Adhesion KW - DNA damage KW - EMT KW - HDACi KW - MET KW - TGFβ SP - 343 EP - 356 JF - Journal of cancer research and clinical oncology JO - J. Cancer Res. Clin. Oncol. VL - 146 IS - 2 N2 - PURPOSE: We set out to determine whether clinically tested epigenetic drugs against class I histone deacetylases (HDACs) affect hallmarks of the metastatic process. METHODS: We treated permanent and primary renal, lung, and breast cancer cells with the class I histone deacetylase inhibitors (HDACi) entinostat (MS-275) and valproic acid (VPA), the replicative stress inducer hydroxyurea (HU), the DNA-damaging agent cis-platinum (L-OHP), and the cytokine transforming growth factor-β (TGFβ). We used proteomics, quantitative PCR, immunoblot, single cell DNA damage assays, and flow cytometry to analyze cell fate after drug exposure. RESULTS: We show that HDACi interfere with DNA repair protein expression and trigger DNA damage and apoptosis alone and in combination with established chemotherapeutics. Furthermore, HDACi disrupt the balance of cell adhesion protein expression and abrogate TGFβ-induced cellular plasticity of transformed cells. CONCLUSION: HDACi suppress the epithelial-mesenchymal transition (EMT) and compromise the DNA integrity of cancer cells. These data encourage further testing of HDACi against tumor cells. SN - 1432-1335 UR - https://www.unboundmedicine.com/medline/citation/31932908/Histone_deacetylase_inhibitors_dysregulate_DNA_repair_proteins_and_antagonize_metastasis-associated_processes L2 - https://dx.doi.org/10.1007/s00432-019-03118-4 DB - PRIME DP - Unbound Medicine ER -
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