耐药性是卵巢癌（OC）高死亡率的主要原因。 BRCA1/2 功能的丧失与 OC 细胞的药物敏感性有关。本研究的目的是通过启动子表观遗传编辑诱导 BRCA1 功能障碍，从而增强 OC 细胞的药物敏感性。 BRCA1 启动子内影响基因表达的表观遗传调控区域最初是通过临床样本分析发现的。随后，我们设计并严格验证了表观遗传编辑工具。最终，我们评估了编辑后 OC 细胞对顺铂和奥拉帕尼的敏感性。 BRCA1 启动子包含两个富含 CpG 的区域，该区域的甲基化覆盖转录起始位点 (TSS)，与转录密切相关，并影响 OC 的发展、预后和同源重组 (HR) 缺陷。使用我们设计的表观遗传编辑工具靶向 OC 细胞中的该区域，导致显着且持久的 DNA 甲基化变化，同时 H3K27ac 组蛋白修饰显着减少。这导致 BRCA1 表达显着抑制和 HR 修复能力下降。因此，编辑后的 ​​OC 细胞对顺铂和奥拉帕尼表现出更高的敏感性，导致细胞凋亡率增加。 BRCA1启动子的表观遗传失活可以通过降低HR修复能力来增强OC细胞对顺铂和奥拉帕尼的敏感性，表明表观遗传编辑技术在OC致敏治疗中的潜在用途。

Drug resistance is the primary contributor to the high mortality rate of ovarian cancer (OC). The loss of BRCA1/2 function is linked to drug sensitivity in OC cells. The aim of this study is to enhance the drug sensitivity of OC cells by inducing BRCA1 dysfunction through promoter epigenetic editing. Epigenetic regulatory regions within the BRCA1 promoter, affecting gene expression, were initially discerned through analysis of clinical samples. Subsequently, we designed and rigorously validated epigenetic editing tools. Ultimately, we evaluated the cisplatin and olaparib sensitivity of the OC cells after editing. The BRCA1 promoter contains two CpG-rich regions, with methylation of the region covering the transcription start site (TSS) strongly correlating with transcription and influencing OC development, prognosis, and homologous recombination (HR) defects. Targeting this region in OC cells using our designed epigenetic editing tools led to substantial and persistent DNA methylation changes, accompanied by significant reductions in H3K27ac histone modifications. This resulted in a notable suppression of BRCA1 expression and a decrease in HR repair capacity. Consequently, edited OC cells exhibited heightened sensitivity to cisplatin and olaparib, leading to increased apoptosis rates. Epigenetic inactivation of the BRCA1 promoter can enhance cisplatin and olaparib sensitivity of OC cells through a reduction in HR repair capacity, indicating the potential utility of epigenetic editing technology in sensitization therapy for OC.