卵巢癌（OCa）是最致命的妇科癌症。新兴数据显示雌激素受体β（ERβ）在卵巢癌中具有肿瘤抑制作用。赖氨酸特异性组蛋白去甲基化酶1A（KDM1A）是一种表观遗传修饰酶，可作为类固醇激素受体的共调节因子。然而，目前尚不清楚KDM1A是否与ERβ相互作用，并在卵巢癌中调控其表达与功能。TCGA数据集的分析表明，在卵巢癌中，KDM1A和ERβ的表达呈负相关，并且KDM1A的敲除、消减或抑制可增加已经建立和患者衍生的卵巢癌细胞的ERβ亚型1的表达。进一步研究发现，KDM1A与ERβ相互作用，并作为其核共抑制子，其抑制可通过改变其启动子上的组蛋白甲基化标记，增强ERβ靶基因的表达。重要的是，KDM1A的敲除或消减增强了ERβ激动剂LY500307的疗效，并且KDM1A抑制剂（KDM1Ai）NCD38与ERβ激动剂的联合治疗通过显著降低卵巢癌细胞的细胞活力、集落形成和侵袭能力产生协同作用。RNA测序和DIA质谱分析显示，KDM1A敲除增强了ERβ信号通路，并且KDM1A敲除与ERβ激动剂共同调节的基因与凋亡、细胞周期和上皮间质转化相关。此外，联合治疗显著降低了原位、同基因和患者衍生异种移植模型中的肿瘤生长以及患者源移植模型中的增殖。我们的结果表明，KDM1A调控ERβ的表达与功能，其抑制改善了ERβ介导的肿瘤抑制作用。总体而言，我们的研究结果表明，KDM1A抑制剂与ERβ激动剂的联合治疗是一种有前景的卵巢癌策略。版权所有 © 2023. Elsevier B.V.出版。

Ovarian cancer (OCa) is the most lethal gynecologic cancer. Emerging data indicates that estrogen receptor beta (ERβ) functions as a tumor suppressor in OCa. Lysine-specific histone demethylase 1A (KDM1A) is an epigenetic modifier that acts as a coregulator for steroid hormone receptors. However, it is unknown if KDM1A interacts with ERβ and regulates its expression/functions in OCa. Analysis of TCGA data sets indicated KDM1A and ERβ expression showed an inverse correlation in OCa, and knockout (KO), knockdown (KD), or inhibition of KDM1A increased ERβ isoform 1 expression in established and patient-derived OCa cells. Further, KDM1A interacts with and functions as a corepressor of ERβ, and its inhibition enhances ERβ target gene expression via alterations of histone methylation marks at their promoters. Importantly, KDM1A-KO or -KD enhanced the efficacy of ERβ agonist LY500307, and the combination of KDM1A inhibitor (KDM1Ai) NCD38 with ERβ agonist synergistically reduced the cell viability, colony formation, and invasion of OCa cells. RNA-seq and DIA mass spectrometry analyses showed that KDM1A-KO resulted in enhanced ERβ signaling and that genes altered by KDM1A-KO and ERβ agonist were related to apoptosis, cell cycle, and EMT. Moreover, combination treatment significantly reduced the tumor growth in orthotopic, syngeneic, and patient-derived xenograft models and proliferation in patient-derived explant models. Our results demonstrate that KDM1A regulates ERβ expression/functions, and its inhibition improves ERβ mediated tumor suppression. Overall, our findings suggest that KDM1Ai and ERβ agonist combination therapy is a promising strategy for OCa.Copyright © 2023. Published by Elsevier B.V.