Pd35-07 Identifying and Targeting Upregulated Histone Modifying Enzymes Involved in Prostate Cancer Cell Survival After Androgen Deprivation Therapy

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III (PD35)1 May 2024PD35-07 IDENTIFYING AND TARGETING UPREGULATED HISTONE MODIFYING ENZYMES INVOLVED IN PROSTATE CANCER CELL SURVIVAL AFTER ANDROGEN DEPRIVATION THERAPY Tanaya Purohit, Emily Schmitt, Marcelo Bigarella, Kayla Bahr, Sean Sardeson, Diana Garcia, Karla Esbona, Peter W. Lewis, John M. Denu, Wei Huang, Bing Yang, and David Jarrard Tanaya PurohitTanaya Purohit , Emily SchmittEmily Schmitt , Marcelo BigarellaMarcelo Bigarella , Kayla BahrKayla Bahr , Sean SardesonSean Sardeson , Diana GarciaDiana Garcia , Karla EsbonaKarla Esbona , Peter W. LewisPeter W. Lewis , John M. DenuJohn M. Denu , Wei HuangWei Huang , Bing YangBing Yang , and David JarrardDavid Jarrard View All Author Informationhttps://doi.org/10.1097/01.JU.0001009396.21455.74.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The cornerstone of advanced prostate cancer (PC) is androgen deprivation therapy (ADT) which induces quiescence, senescence, but rarely apoptosis. Persistent cancer cells lead to castration resistance. Aberrant expression of specific histone modifying enzymes (HME) that regulate histone post-translational modifications and gene pathways may be important in cancer cell survival after ADT. We seek to identify upregulated HMEs in PC patients during early ADT, which are hypothesized to be essential for tumor cell survival and potential targets for synergistic inhibition. METHODS: RNA-seq was used to evaluate the altered expression of 95 HMEs in 10 ADT-treated neoadjuvant(3mos) and 26 untreated high-risk PC samples. Upregulated HMEs in ADT-treated tumors were validated using two publicly available expression datasets(n=11;n=9). Candidate HME protein expression was examined in ADT-treated LNCaP cells by Western. A tissue microarray(TMA) was constructed from 32 ADT-treated and 29 untreated post-prostatectomy samples to evaluate EZH1 expression with immunohistochemistry. LNCaP cells were exposed to the EZH1/2 FDA-approved inhibitor Valemetostat± ADT and synergy was calculated (Calcusyn™). RESULTS: Compared to untreated tumors, ADT-treated samples upregulate 18 candidate HMEs in RNA-seq data. Analysis of ADT-treated samples in the public datasets validated the upregulation of four HMEs: EZH1, MECOM, HDAC5, and PRDM16 (p<0.1). EZH1, a histone methyltransferase within the PRC2 complex, increases in LNCaP cells up to 2 weeks after ADT exposure. Comparing ADT-treated and untreated PC tumors reveal a persistence of EZH1 expression at 3mo after ADT (24 % vs 26%, respectively). Combination therapy with Valemetostat± ADT did not demonstrate a synergistic effect in LNCaP cells . Days to PSA recurrence negatively correlated with EZH1 expression in the ADT-treated PC tumors(r=-0.22) suggesting that high expression of EZH1 might predict worse patient outcomes. CONCLUSIONS: We identified EZH1 as a HME with persistent/upregulated expression in PC after ADT treatment. EZH1 is a histone methyltransferase involved in preventing senescence that represents a potential enzyme target (when specifically, targeted) when combined with ADT to improve tumor responses. Download PPT Source of Funding: None © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e727 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Tanaya Purohit More articles by this author Emily Schmitt More articles by this author Marcelo Bigarella More articles by this author Kayla Bahr More articles by this author Sean Sardeson More articles by this author Diana Garcia More articles by this author Karla Esbona More articles by this author Peter W. Lewis More articles by this author John M. Denu More articles by this author Wei Huang More articles by this author Bing Yang More articles by this author David Jarrard More articles by this author Expand All Advertisement PDF downloadLoading ...