USP11 通过上调 AR 和 c-Myc 活性促进前列腺癌进展。

USP11 promotes prostate cancer progression by up-regulating AR and c-Myc activity.

机构信息

Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD 21201.

Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201.

出版信息

Proc Natl Acad Sci U S A. 2024 Jul 30;121(31):e2403331121. doi: 10.1073/pnas.2403331121. Epub 2024 Jul 25.

Androgen receptor (AR) is a main driver for castration-resistant prostate cancer (CRPC). c-Myc is an oncogene underlying prostate tumorigenesis. Here, we find that the deubiquitinase USP11 targets both AR and c-Myc in prostate cancer (PCa). USP11 expression was up-regulated in metastatic PCa and CRPC. USP11 knockdown (KD) significantly inhibited PCa cell growth. Our RNA-seq studies revealed AR and c-Myc as the top transcription factors altered after USP11 KD. ChIP-seq analysis showed that either USP11 KD or replacement of endogenous USP11 with a catalytic-inactive USP11 mutant significantly decreased chromatin binding by AR and c-Myc. We find that USP11 employs two mechanisms to up-regulate AR and c-Myc levels: namely, deubiquitination of AR and c-Myc proteins to increase their stability and deubiquitination of H2A-K119Ub, a repressive histone mark, on promoters of AR and c-Myc genes to increase their transcription. AR and c-Myc reexpression in USP11-KD PCa cells partly rescued cell growth defects. Thus, our studies reveal a tumor-promoting role for USP11 in aggressive PCa through upregulation of AR and c-Myc activities and support USP11 as a potential target against PCa.

雄激素受体（AR）是去势抵抗性前列腺癌（CRPC）的主要驱动因素。c-Myc 是前列腺肿瘤发生的癌基因。在这里，我们发现去泛素化酶 USP11 是前列腺癌（PCa）中 AR 和 c-Myc 的主要靶点。USP11 的表达在转移性 PCa 和 CRPC 中上调。USP11 敲低（KD）显著抑制 PCa 细胞生长。我们的 RNA-seq 研究表明，USP11 KD 后，AR 和 c-Myc 是转录因子变化最大的两个。ChIP-seq 分析表明，USP11 KD 或用催化失活的 USP11 突变体取代内源性 USP11，均显著降低了 AR 和 c-Myc 的染色质结合。我们发现 USP11 通过两种机制上调 AR 和 c-Myc 水平：即 AR 和 c-Myc 蛋白的去泛素化，以增加其稳定性，以及 H2A-K119Ub 的去泛素化，H2A-K119Ub 是 AR 和 c-Myc 基因启动子上的一种抑制性组蛋白标记，以增加其转录。USP11-KD PCa 细胞中 AR 和 c-Myc 的重新表达部分挽救了细胞生长缺陷。因此，我们的研究揭示了 USP11 通过上调 AR 和 c-Myc 的活性在侵袭性 PCa 中发挥促肿瘤作用，并支持 USP11 作为对抗 PCa 的潜在靶点。