Combating castration-resistant prostate cancer by co-targeting the epigenetic regulators EZH2 and HDAC
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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-04-01
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| Series: | PLoS Biology |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138213/?tool=EBI |
| _version_ | 1797836122314768384 |
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| author | Amy E. Schade Ryan Kuzmickas Carrie L. Rodriguez Kaia Mattioli Miriam Enos Alycia Gardner Karen Cichowski |
| author_facet | Amy E. Schade Ryan Kuzmickas Carrie L. Rodriguez Kaia Mattioli Miriam Enos Alycia Gardner Karen Cichowski |
| author_sort | Amy E. Schade |
| collection | DOAJ |
| description | 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. Epigenetic, transcriptional, and functional studies show that two major epigenetic regulators (EZH2 and HDAC) buffer advanced prostate cancer from lethal stress responses, revealing a promising combination therapy for castration-resistant disease. |
| first_indexed | 2024-04-09T15:03:35Z |
| format | Article |
| id | doaj.art-fe482346ab9d432395397099fc6b4c1d |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-04-09T15:03:35Z |
| publishDate | 2023-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-fe482346ab9d432395397099fc6b4c1d2023-05-01T05:30:51ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852023-04-01214Combating castration-resistant prostate cancer by co-targeting the epigenetic regulators EZH2 and HDACAmy E. SchadeRyan KuzmickasCarrie L. RodriguezKaia MattioliMiriam EnosAlycia GardnerKaren CichowskiWhile 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. Epigenetic, transcriptional, and functional studies show that two major epigenetic regulators (EZH2 and HDAC) buffer advanced prostate cancer from lethal stress responses, revealing a promising combination therapy for castration-resistant disease.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138213/?tool=EBI |
| spellingShingle | Amy E. Schade Ryan Kuzmickas Carrie L. Rodriguez Kaia Mattioli Miriam Enos Alycia Gardner Karen Cichowski Combating castration-resistant prostate cancer by co-targeting the epigenetic regulators EZH2 and HDAC PLoS Biology |
| title | Combating castration-resistant prostate cancer by co-targeting the epigenetic regulators EZH2 and HDAC |
| title_full | Combating castration-resistant prostate cancer by co-targeting the epigenetic regulators EZH2 and HDAC |
| title_fullStr | Combating castration-resistant prostate cancer by co-targeting the epigenetic regulators EZH2 and HDAC |
| title_full_unstemmed | Combating castration-resistant prostate cancer by co-targeting the epigenetic regulators EZH2 and HDAC |
| title_short | Combating castration-resistant prostate cancer by co-targeting the epigenetic regulators EZH2 and HDAC |
| title_sort | combating castration resistant prostate cancer by co targeting the epigenetic regulators ezh2 and hdac |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138213/?tool=EBI |
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