Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Biomed Pharmacother. 2023 Feb;158:114077. doi: 10.1016/j.biopha.2022.114077. Epub 2022 Dec 7.
Epigenetics is an emerging mechanism for tumorigenesis. Treatment that targets epigenetic regulators is becoming an attractive strategy for cancer therapy. The role of epigenetic therapy in prostate cancer (PCa) remains elusive. Previously we demonstrated that upregulation of histone lysine demethylase KDM4B correlated with the appearance of castration resistant prostate cancer (CRPC) and identified a small molecular inhibitor of KDM4B, B3. In this study, we further investigated the role of KDM4B in promoting PCa progression and tested the efficacy of B3 using clinically relevant PCa models including PCa cell line LNCaP and 22Rv1 and xenografts derived from these cell lines. In loss and gain-functional studies of KDM4B in PCa cells, we found that overexpression of KDM4B in LNCaP cells enhanced its tumorigenicity whereas knockdown of KDM4B in 22Rv1 cells reduced tumor growth in castrated mice. B3 suppressed the growth of 22Rv1 xenografts and sensitized tumor to anti-androgen receptor (AR) antagonist enzalutamide inhibition. B3 also inhibited 22Rv1 tumor growth synergistically with rapamycin, leading to cell apoptosis. Comparative transcriptomic analysis performed on KDM4B knockdown and B3-treated 22Rv1 cells revealed that B3 inhibited both H3K9me3 and H3K27me3 demethylase activities. Our studies establish KDM4B as a target for CRPC and B3 as a potential therapeutic agent. B3 as monotherapy or in combination with other anti-PCa therapeutics offers proof of principle for the clinical translation of epigenetic therapy targeting KDMs for CRPC patients.
表观遗传学是肿瘤发生的一个新兴机制。针对表观遗传调节剂的治疗正成为癌症治疗的一种有吸引力的策略。表观遗传学治疗在前列腺癌（PCa）中的作用仍难以捉摸。我们之前证明组蛋白赖氨酸去甲基酶 KDM4B 的上调与去势抵抗性前列腺癌（CRPC）的出现相关，并鉴定了 KDM4B 的小分子抑制剂 B3。在这项研究中，我们进一步研究了 KDM4B 在促进 PCa 进展中的作用，并使用包括 PCa 细胞系 LNCaP 和 22Rv1 以及源自这些细胞系的异种移植物在内的临床相关 PCa 模型测试了 B3 的疗效。在 PCa 细胞中 KDM4B 的缺失和功能获得研究中，我们发现 LNCaP 细胞中 KDM4B 的过表达增强了其致瘤性，而 22Rv1 细胞中 KDM4B 的敲低则降低了去势小鼠中的肿瘤生长。B3 抑制了 22Rv1 异种移植物的生长，并使肿瘤对雄激素受体（AR）拮抗剂恩杂鲁胺抑制敏感。B3 还与雷帕霉素协同抑制 22Rv1 肿瘤生长，导致细胞凋亡。在 KDM4B 敲低和 B3 处理的 22Rv1 细胞上进行的比较转录组分析表明，B3 抑制了 H3K9me3 和 H3K27me3 去甲基酶活性。我们的研究确立了 KDM4B 为 CRPC 的靶点，B3 为潜在的治疗剂。B3 作为单一疗法或与其他抗 PCa 治疗联合使用，为针对 CRPC 患者的 KDM 靶向表观遗传学治疗的临床转化提供了原理证明。
