Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List

Full text release has been delayed at the author's request until May 31, 2024

ETD Abstract Container

Abstract Header

Discovery of a Novel Class of Agents that Inhibit EZH2 Activity and Lowers the Expression of Androgen Receptor and their Potential Utility in the Treatment of Castration-Resistant Prostate Cancer

Han, Zhengyang
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1682945564133313

Abstract Details

2023, Doctor of Philosophy, University of Toledo, Biology (Cell-Molecular Biology).
Prostate cancer is the second leading cause of cancer related deaths among male in the western world. Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer. Androgen-deprivation therapy (ADT) has been used to treat early-stage prostate cancer. However, since prostate cancer will usually develop into castration-resistant prostate cancer (CRPC), drugs such as Enzalutamide and Abiraterone have been developed to target CRPC. Despite having these widely used drugs, most patients will develop resistance to these drugs that results in a lethal form of CRPC. Therefore, new targets for resistant CRPC are needed. EZH2 has emerged as a promising target for prostate cancer. EZH2 is part of the polycomb repressive complex 2 (PRC2), it methylates Histone H3K27. It plays an important role in prostate cancer development, with the methylation dependent function of EZH2 involved in silencing tumor suppressor genes. Methylation-independent function of EZH2 can lead to the transcriptional activation of oncogenes and AR. Several EZH2 inhibitors have been developed, however these inhibitors only target the methylation-dependent functions of EZH2, which are not promising for treating prostate cancer. In this study, we identified a novel class of agents that inhibits both methylation-dependent and methylation-independent functions of EZH2 by binding to SUZ12 of PRC2, that display strong cytotoxicity for drug-resistant CRPC. These peptides were shown to bind to the SUZ12 VEFS domain and have the unique ability to inhibit both EZH2 enzyme activity and AR expression, which led to strong cytotoxicity towards prostate cancer cells, including importantly Enzalutamide-resistant prostate cancer cells. The dual functions and cytotoxic activity of these peptides makes them attractive candidates for development into a possible new effective therapy for CRPC, but peptides make poor drugs for several reasons. Thus, we developed a peptide displacement assay to screen a fragment library and identified several small molecules that bind to the SUZ12 VEFS domain, where active peptides bind. These small molecules were able to inhibit EZH2 enzyme activity and are cytotoxic toward prostate cancer cells. This is an encouraging starting point that may allow us to develop dual-acting drugs that are effective against drug-resistant CRPC and in the future can be tested in pre-clinical and clinical studies.
Lirim Shemshedini (Committee Chair)
Scott Leisner (Committee Member)
Isaac Schiefer (Committee Member)
Ron Viola (Committee Member)
Deborah Chad (Committee Member)
Molecular Biology
prostate cancer, EZH2

Recommended Citations

Citations

  • Han, Z. (2023). Discovery of a Novel Class of Agents that Inhibit EZH2 Activity and Lowers the Expression of Androgen Receptor and their Potential Utility in the Treatment of Castration-Resistant Prostate Cancer [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1682945564133313

    APA Style (7th edition)

  • Han, Zhengyang. Discovery of a Novel Class of Agents that Inhibit EZH2 Activity and Lowers the Expression of Androgen Receptor and their Potential Utility in the Treatment of Castration-Resistant Prostate Cancer. 2023. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1682945564133313.

    MLA Style (8th edition)

  • Han, Zhengyang. "Discovery of a Novel Class of Agents that Inhibit EZH2 Activity and Lowers the Expression of Androgen Receptor and their Potential Utility in the Treatment of Castration-Resistant Prostate Cancer." Doctoral dissertation, University of Toledo, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1682945564133313

    Chicago Manual of Style (17th edition)

toledo1682945564133313
© 2023, some rights reserved.Creative Commons License Discovery of a Novel Class of Agents that Inhibit EZH2 Activity and Lowers the Expression of Androgen Receptor and their Potential Utility in the Treatment of Castration-Resistant Prostate Cancer by Zhengyang Han is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Toledo and OhioLINK.