دورية أكاديمية
Combating castration-resistant prostate cancer by co-targeting the epigenetic regulators EZH2 and HDAC.
| العنوان: | Combating castration-resistant prostate cancer by co-targeting the epigenetic regulators EZH2 and HDAC. |
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| المؤلفون: | Amy E Schade, Ryan Kuzmickas, Carrie L Rodriguez, Kaia Mattioli, Miriam Enos, Alycia Gardner, Karen Cichowski |
| المصدر: | PLoS Biology, Vol 21, Iss 4, p e3002038 (2023) |
| بيانات النشر: | Public Library of Science (PLoS), 2023. |
| سنة النشر: | 2023 |
| المجموعة: | LCC:Biology (General) |
| مصطلحات موضوعية: | Biology (General), QH301-705.5 |
| الوصف: | While screening and early detection have reduced mortality from prostate cancer, castration-resistant disease (CRPC) is still incurable. Here, we report that combined EZH2/HDAC inhibitors potently kill CRPCs and cause dramatic tumor regression in aggressive human and mouse CRPC models. Notably, EZH2 and HDAC both transmit transcriptional repressive signals: regulating histone H3 methylation and histone deacetylation, respectively. Accordingly, we show that suppression of both EZH2 and HDAC are required to derepress/induce a subset of EZH2 targets, by promoting the sequential demethylation and acetylation of histone H3. Moreover, we find that the induction of one of these targets, ATF3, which is a broad stress response gene, is critical for the therapeutic response. Importantly, in human tumors, low ATF3 levels are associated with decreased survival. Moreover, EZH2- and ATF3-mediated transcriptional programs inversely correlate and are most highly/lowly expressed in advanced disease. Together, these studies identify a promising therapeutic strategy for CRPC and suggest that these two major epigenetic regulators buffer prostate cancers from a lethal response to cellular stresses, thereby conferring a tractable therapeutic vulnerability. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1544-9173 1545-7885 |
| Relation: | https://doaj.org/toc/1544-9173; https://doaj.org/toc/1545-7885 |
| DOI: | 10.1371/journal.pbio.3002038 |
| URL الوصول: | https://doaj.org/article/cbbf2f8fe5bb48b684463c3b2ea4080e |
| رقم الأكسشن: | edsdoj.bbf2f8fe5bb48b684463c3b2ea4080e |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 15449173 15457885 |
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| DOI: | 10.1371/journal.pbio.3002038 |