美国加州大学Felix Y. Feng团队报道了基因组级CRISPR筛选鉴定PTGES3是晚期前列腺癌雄激素受体功能的直接调节剂。2025年11月5日出版的《自然—遗传学》杂志发表了这项成果。

为了研究AR蛋白水平和致癌活性的调节因子，该研究团队开发了一种活细胞内源性AR荧光定量报告细胞。利用这个AR报告基因，课题组研究人员进行了基因组规模的CRISPRi流式细胞术筛选，系统地鉴定了调节AR蛋白水平的基因。该研究组鉴定并验证了已知的AR蛋白调控因子，包括HOXB13和GATA2，以及意想不到的顶级靶点，包括PTGES3——PCa中一个特征不明显的基因。在AR驱动的PCa模型中，PTGES3抑制导致AR蛋白缺失、细胞周期阻滞和细胞死亡。临床上，PCa数据分析表明PTGES3表达与AR靶向治疗耐药相关。在机制上，研究小组发现PTGES3直接与AR结合，调节AR蛋白的稳定性，并且是AR靶基因核仁中AR功能的必要条件。PTGES3代表了一个潜在的治疗靶点，可以克服PCa中对现有AR导向疗法的已知耐药机制。

据悉，雄激素受体（AR）是前列腺癌（PCa）的关键驱动因子。

附：英文原文

Title: Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer

Author: Li, Haolong, Melnyk, James E., Fu, Becky Xu Hua, Shrestha, Raunak, Zhang, Meng, Sjstrm, Martin, Feng, Siyu, Anderson, Jasmine A., Han, Wanting, Chesner, Lisa N., Shin, Hyun Jin, Farsh, Tatyanah, Suarez, Humberto J., Nath, Seema, Chou, Jonathan, Das, Rajdeep, Egusa, Emily A., Calvert, Marsha, Kishishita, Audrey, Barpanda, Abhilash, Zhu, Jun, Maheshwari, Ashutosh, Chen, William S., Alshalalfa, Mohammed, Winters, Aidan, Hua, Junjie T., Liu, Tianyi, Davicioni, Elai, Wiita, Arun P., Stohr, Bradley A., Siddiqui, Javed, Huang, Bo, Small, Eric J., Shokat, Kevan M., Nelson, Peter S., Quigley, David A., Wasmuth, Elizabeth V., Gilbert, Luke A., Feng, Felix Y.

Issue&Volume: 2025-11-05

Abstract: The androgen receptor (AR) is a critical driver of prostate cancer (PCa). Here, to study regulators of AR protein levels and oncogenic activity, we developed a live-cell quantitative endogenous AR fluorescent reporter. Leveraging this AR reporter, we performed genome-scale CRISPRi flow cytometry sorting screens to systematically identify genes that modulate AR protein levels. We identified and validated known AR protein regulators, including HOXB13 and GATA2, and also unexpected top hits including PTGES3—a poorly characterized gene in PCa. PTGES3 repression resulted in loss of AR protein, cell-cycle arrest and cell death in AR-driven PCa models. Clinically, analysis of PCa data demonstrates that PTGES3 expression is associated with AR-directed therapy resistance. Mechanistically, we show PTGES3 binds directly to AR, regulates AR protein stability and is necessary for AR function in the nucleus at AR target genes. PTGES3 represents a potential therapeutic target for overcoming known mechanisms of resistance to existing AR-directed therapies in PCa.

DOI: 10.1038/s41588-025-02388-8

Source: https://www.nature.com/articles/s41588-025-02388-8