Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2.
| Title: | Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2. |
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| Authors: | Labaf M; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.; Department of Mathematics, University of Massachusetts Boston, Boston, MA, United States.; Li M; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.; Department of Biology, University of Massachusetts Boston, Boston, MA, United States.; Ting L; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.; Department of Biology, University of Massachusetts Boston, Boston, MA, United States.; Karno B; Department of Medicine, Vanderbilt University, Nashville, TN, United States.; Zhang S; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.; Department of Biology, University of Massachusetts Boston, Boston, MA, United States.; Gao S; Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, United States.; Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, United States.; Patalano S; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.; Department of Biology, University of Massachusetts Boston, Boston, MA, United States.; Macoska JA; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.; Department of Biology, University of Massachusetts Boston, Boston, MA, United States.; Zarringhalam K; Department of Mathematics, University of Massachusetts Boston, Boston, MA, United States.; Han D; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.; Department of Biology, University of Massachusetts Boston, Boston, MA, United States.; Cai C; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.; Department of Biology, University of Massachusetts Boston, Boston, MA, United States. |
| Source: | Frontiers in oncology [Front Oncol] 2022 Nov 03; Vol. 12, pp. 1021845. Date of Electronic Publication: 2022 Nov 03 (Print Publication: 2022). |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101568867 Publication Model: eCollection Cited Medium: Print ISSN: 2234-943X (Print) Linking ISSN: 2234943X NLM ISO Abbreviation: Front Oncol Subsets: PubMed not MEDLINE |
| Imprint Name(s): | Original Publication: [Lausanne : Frontiers Research Foundation] |
| Abstract: | Elevated androgen receptor (AR) expression is a hallmark of castration-resistant prostate cancer (CRPC) and contributes to the restoration of AR signaling under the conditions of androgen deprivation. However, whether overexpressed AR alone with the stimulation of castrate levels of androgens can be sufficient to induce the reprogramming of AR signaling for the adaptation of prostate cancer (PCa) cells remains unclear. In this study, we used a PCa model with inducible overexpression of AR to examine the acute effects of AR overexpression on its cistrome and transcriptome. Our results show that overexpression of AR alone in conjunction with lower androgen levels can rapidly redistribute AR chromatin binding and activates a distinct transcription program that is enriched for DNA damage repair pathways. Moreover, using a recently developed bioinformatic tool, we predicted the involvement of EZH2 in this AR reprogramming and subsequently identified a subset of AR/EZH2 co-targeting genes, which are overexpressed in CRPC and associated with worse patient outcomes. Mechanistically, we found that AR-EZH2 interaction is impaired by the pre-castration level of androgens but can be recovered by the post-castration level of androgens. Overall, our study provides new molecular insights into AR signaling reprogramming with the engagement of specific epigenetic factors.; (Copyright © 2022 Labaf, Li, Ting, Karno, Zhang, Gao, Patalano, Macoska, Zarringhalam, Han and Cai.) |
| Competing Interests: | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. |
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| Grant Information: | R01 CA211350 United States CA NCI NIH HHS; U54 CA156734 United States CA NCI NIH HHS |
| Contributed Indexing: | Keywords: AR; CRPC; DNA damage repair; EZH2; androgen; androgen receptor; androgen-deprivation therapy; prostate cancer |
| Entry Date(s): | Date Created: 20221121 Latest Revision: 20250401 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC9669968 |
| DOI: | 10.3389/fonc.2022.1021845 |
| PMID: | 36408179 |
| Database: | MEDLINE |
Journal Article