EZH2 Loss Drives Resistance to Carboplatin and Paclitaxel in Serous Ovarian Cancers Expressing ATM
| Autor: | Tanja Fehm, Martin Schlensog, Diethelm Wallwiener, I. Beyer, Johanna Naskou, Sara Y. Brucker, Ellen Honisch, Annette Staebler, Martina Rudelius, Silvia Darb-Esfahani, Ruan van Rensburg, Hans Neubauer, Dieter Niederacher, Markus F. Templin, Elena Ioana Braicu, Yvonne Beiter, Julia Gottstein, Andreas D. Hartkopf, Jalid Sehouli, Larissa Walter |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Paclitaxel Ataxia Telangiectasia Mutated Proteins macromolecular substances Proximity ligation assay Carboplatin 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Humans Neoplasm Enhancer of Zeste Homolog 2 Protein RNA Messenger Molecular Biology Survival analysis Aged Ovarian Neoplasms business.industry EZH2 DNA Neoplasm medicine.disease Cystadenocarcinoma Serous Serous fluid 030104 developmental biology Oncology chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Female business Ovarian cancer DNA Damage Signal Transduction |
| Zdroj: | Molecular Cancer Research. 18:278-286 |
| ISSN: | 1557-3125 1541-7786 |
| DOI: | 10.1158/1541-7786.mcr-19-0141 |
| Popis: | Mechanisms of intrinsic resistance of serous ovarian cancers to standard treatment with carboplatin and paclitaxel are poorly understood. Seventeen primary serous ovarian cancers classified as responders or nonresponders to standard treatment were screened with DigiWest protein array analysis for 279 analytes. Histone methyl transferase EZH2, an interaction partner of ataxia telangiectasia mutated (ATM), was found as one of the most significantly represented proteins in responsive tumors. Survival analysis of 616 patients confirmed a better outcome in patients with high EZH2 expression, but a worse outcome in patients with low EZH2 and high-ATM–expressing tumors compared with patients with low EZH2 and low-ATM–expressing tumors. A proximity ligation assay further confirmed an association between ATM and EZH2 in tumors of patients with an increased disease-free survival. Knockdown of EZH2 resulted in treatment-resistant cells, but suppression of both EZH2 and ATM, or ATM alone, had no effect. DigiWest protein analysis of EZH2-knockdown cells revealed a decrease in proteins involved in mitotic processes and checkpoint regulation, suggesting that deregulated ATM may induce treatment resistance. Implications: Ovarian cancer is a malignancy with high mortality rates, with to date, no successful molecular characterization strategies. Our study uncovers in a comprehensive approach the involvement of checkpoint regulation via ATM and EZH2, potentially providing a new therapeutic perspective for further investigations. |
| Databáze: | OpenAIRE |
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