PO.ET06.05 · 实验与分子治疗

雄激素剥夺前列腺癌中的组蛋白修饰酶：EZH1作为协同治疗靶点

Histone-modifying enzymes in androgen-deprived prostate cancer: EZH1 as a synergistic therapeutic target

编号 5715 展板 4 时间 4/21 02:00–05:00 区域 Section 13 主讲 Emily Schmitt, BS

分会场 Molecular Targets 2

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作者与单位 Authors & Affiliations

Tanaya Purohit¹, Emily Schmitt¹, Zachary Schultz¹, Marcelo Bigarella¹, Kayla Bahr¹, Mohammad Rizvi¹, Diana Garcia¹, Sean Sardeson¹, Erika Heninger², Shannon Reese², Jacob Popp², Joshua M. Lang³, Karla Esbona⁴, Wei Huang⁴, Peter W. Lewis⁵, John M. Denu⁵, Bing Yang¹, David F. Jarrard¹

¹Department of Urology, University of Wisconsin-Madison, Madison, WI,²Department of Medicine, Division of Hematology-Oncology, University of Wisconsin-Madison, Madison, WI,³University of Wisconsin Carbone Cancer Center, Madison, WI,⁴Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI,⁵Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI

摘要 Abstract

中文摘要

背景：雄激素剥夺治疗（ADT）是晚期前列腺癌（PC）治疗的基石。虽然ADT诱导凋亡和衰老，但残留肿瘤细胞常持续存在并驱动去势抵抗。ADT的启动可能产生可被治疗性利用的易感性。我们研究了组蛋白修饰酶（HMEs）在ADT后支持肿瘤细胞存活中的作用，假设其上调有助于持留并代表一个协同治疗的靶点。方法：使用bulk RNA测序将接受3个月ADT治疗的高危前列腺切除术样本与未治疗对照进行比较（n=10 vs. 26）。查询了公开可用的数据集（Wyatt GSE550162；Sowalsky GSE1831003）以进行验证。通过Western blotting在不同时间点评估经ADT（CSS：活性炭吸附血清）处理的激素敏感性PC（HSPC）细胞系LNCaP、LAPC4和VCaP中EZH1/2和H3K27me3的表达。构建组织芯片，使用免疫组织化学以及自动化VECTRA成像和定量，在30例ADT治疗和29例未治疗的前列腺切除术后HSPC肿瘤中评估EZH1的蛋白表达。用bicalutamide（比卡鲁胺）或darolutamide（达罗他胺）联合dox诱导型EZH1 shRNA或FDA批准的EZH1/2抑制剂valemetostat处理HSPC细胞系和患者来源类器官，以检测对细胞生长的协同抑制。结果：高危前列腺切除术样本识别出四个在ADT后持续上调的HMEs：EZH1、MECOM、SIRT1，以及GCN5、KDM6B、PRDM5/6/16。其中，EZH1和MECOM在59例患者的验证组织芯片中随ADT显示出蛋白表达增加，EZH1在ADT治疗队列中与不良临床特征（包括PSA复发）相关。在LNCaP和VCaP细胞系中，EZH1表达在早期ADT后升高或持续，而EZH2下降，伴随H3K27甲基化水平升高。总H3K27me3水平增加。EZH1表达与一部分EMT和干细胞标志物呈正相关。EZH1敲低降低了ADT处理细胞的存活，患者来源类器官模型显示，bicalutamide或darolutamide与EZH1/2抑制（valemetostat）联合可产生协同细胞死亡。结论：ADT诱导EZH1上调，后者可能通过调控癌症干性和上皮-间质转化促进前列腺癌细胞持留。这些发现确立了EZH1作为ADT后存活的介导者以及协同治疗抑制的有前景靶点。资助致谢：本研究部分由DoD PC150211、UW Prostate SPORE P50CA269011以及NIH/NCI R01CA76184、P30 CA014520资助。利益冲突：无。

查看英文原文 English abstract

Background: Androgen deprivation therapy (ADT) is the cornerstone of treatment for advanced prostate cancer (PC). While ADT induces apoptosis and senescence, residual tumor cells frequently persist and drive castration resistance. The initiation of ADT may create vulnerabilities that can be therapeutically exploited. We investigated the role of histone-modifying enzymes (HMEs) in supporting tumor cell survival after ADT, hypothesizing that their upregulation contributes to persistence and represents a target for synergistic therapy. Methods: High-risk prostatectomy samples treated with 3 months of ADT were compared to untreated controls using bulk RNA sequencing (n=10 vs. 26). Publicly available datasets (Wyatt GSE550162; Sowalsky GSE1831003) were interrogated for validation. The expression of EZH1/2 and H3K27me3 was assessed in hormone-sensitive PC (HSPC) cell lines LNCaP, LAPC4 and VCaP treated with ADT (CSS: charcoal-stripped serum) at different timepoints by Western blotting. A tissue microarray was constructed to evaluate the protein expression of EZH1 in 30 ADT-treated and 29 untreated post-prostatectomy HSPC tumors using immunohistochemistry and automated VECTRA imaging and quantification. HSPC cell lines and patient-derived organoids were treated with bicalutamide or darolutamide in combination with dox-inducible EZH1 shRNAs or FDA-approved EZH1/2 inhibitor valemetostat to examine synergistic inhibition of cell growth. Results: High-risk prostatectomy samples identified four consistently upregulated HMEs: EZH1, MECOM, SIRT1, and GCN5, KDM6B, PRDM5/6/16 after ADT. Among these, EZH1 and MECOM showed increased protein expression with ADT in a validation tissue microarray of 59 patients with EZH1 correlated with adverse clinical features including and PSA recurrence in the ADT-treated cohort. In LNCaP and VCaP cell lines EZH1 expression rose or persisted after early ADT, while EZH2 declined with increased H3K27 methylation levels. Total H3K27me3 levels increased. EZH1 expression positively associates with a subset of EMT and stem cell markers. EZH1 knockdown reduced survival of ADT-treated cells, and patient-derived organoid models showed synergistic cell death with combined either bicalutamide or darolutamide and EZH1/2 inhibition (valemetostat). Conclusions: ADT induces EZH1 upregulation, which promotes prostate cancer cell persistence potentially through regulation of cancer stemness and epithelial-to-mesenchymal transition. These findings establish EZH1 as a mediator of survival after ADT and a promising target for synergistic therapeutic inhibition. Funding Acknowledgements: This study was supported in part by DoD PC150211, UW Prostate SPORE P50CA269011, and NIH/NCIR01CA76184, P30 CA014520. COI: none

利益披露 Disclosure

T. Purohit, None.. E. Schmitt, None.. Z. Schultz, None.. M. Bigarella, None.. K. Bahr, None.. M. Rizvi, None.. D. Garcia, None.. S. Sardeson, None.. E. Heninger, None.. S. Reese, None.. J. Popp, None.. J. M. Lang, None.. K. Esbona, None.. W. Huang, None.. P. W. Lewis, None.. J. M. Denu, None.. B. Yang, None.. D. F. Jarrard, None.

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