卵巢癌（OCa）是所有妇科癌症中最致命的。 OCa 的标准治疗是铂类化疗，例如卡铂或顺铂联合紫杉醇。大多数患者最初对这些治疗有反应；然而，近 90% 的患者会出现复发并不可避免地死于化疗耐药性疾病。最近的研究表明，表观遗传修饰剂赖氨酸特异性组蛋白去甲基酶 1A (KDM1A/LSD1) 在 OCa 中高度过表达。然而，KDM1A 在化疗耐药中的作用以及其抑制是否会增强 OCa 的化疗反应仍不确定。 TCGA 数据集分析显示，对化疗反应不佳的患者中 KDM1A 表达较高。 Western blot 分析显示，化疗药物顺铂、卡铂和紫杉醇治疗可增加 OCa 细胞中 KDM1A 的表达。 KDM1A 敲低 (KD) 或用 KDM1A 抑制剂 NCD38 和 SP2509 治疗可使已建立的 OCa 细胞和患者来源的 OCa 细胞对化疗药物敏感，从而降低细胞活力和克隆存活并诱导细胞凋亡。此外，KDM1A 的敲低使卡铂耐药 A2780-CP70 细胞对卡铂治疗敏感，紫杉醇耐药 SKOV3-TR 细胞对紫杉醇敏感。 RNA-seq 分析显示，KDM1A-KD 和顺铂联合治疗导致与上皮间质转化 (EMT) 相关的基因下调。有趣的是，顺铂治疗增加了 NF-κB 通路基因的子集，而 KDM1A-KD 或 KDM1A 抑制逆转了这种效应。重要的是，在原位滑囊内 OCa 异种移植模型中，与单一治疗相比，KDM1A-KD 与顺铂联合显着减少了肿瘤生长。总的来说，这些发现表明 KDM1A 抑制剂与化疗的组合可能是治疗 OCa 的一种有前途的治疗方法。© 2024 Wiley periodicals LLC。

Ovarian cancer (OCa) is the deadliest of all gynecological cancers. The standard treatment for OCa is platinum-based chemotherapy, such as carboplatin or cisplatin in combination with paclitaxel. Most patients are initially responsive to these treatments; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. Recent studies have revealed that the epigenetic modifier lysine-specific histone demethylase 1A (KDM1A/LSD1) is highly overexpressed in OCa. However, the role of KDM1A in chemoresistance and whether its inhibition enhances chemotherapy response in OCa remains uncertain. Analysis of TCGA datasets revealed that KDM1A expression is high in patients who poorly respond to chemotherapy. Western blot analysis show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A knockdown (KD) or treatment with KDM1A inhibitors NCD38 and SP2509 sensitized established and patient-derived OCa cells to chemotherapy drugs in reducing cell viability and clonogenic survival and inducing apoptosis. Moreover, knockdown of KDM1A sensitized carboplatin-resistant A2780-CP70 cells to carboplatin treatment and paclitaxel-resistant SKOV3-TR cells to paclitaxel. RNA-seq analysis revealed that a combination of KDM1A-KD and cisplatin treatment resulted in the downregulation of genes related to epithelial-mesenchymal transition (EMT). Interestingly, cisplatin treatment increased a subset of NF-κB pathway genes, and KDM1A-KD or KDM1A inhibition reversed this effect. Importantly, KDM1A-KD, in combination with cisplatin, significantly reduced tumor growth compared to a single treatment in an orthotopic intrabursal OCa xenograft model. Collectively, these findings suggest that combination of KDM1A inhibitors with chemotherapy could be a promising therapeutic approach for the treatment of OCa.© 2024 Wiley Periodicals LLC.