![Sample our Bioscience journals, sign in here to start your access, Latest two full volumes FREE to you for 14 days]({"type":"image" , "src" : "/sda/5925/TOC-Subject-Sample-2021-Bioscience.jpg"})
ABSTRACT
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.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Availability of data and materials
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Author contributions
XN and QW designed the study. WH, HZ and QW collected the data from databases and performed analyses. WH, HZ and QW organized and arranged all the figures. WH, HZ and SZ performed the experiments and the formal analysis. GS, HL, MW and GY collected tissue samples. WH and QW prepared and wrote the original draft of the manuscript. XN reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.
Ethics approval and consent to participate
The studies involving human participants were reviewed and approved by the Xiangya School of Medicine, Central South University (approval no. 2019030306). The patients/participants provided their written informed consent to participate in this study. The study was conducted in accordance with the Declaration of Helsinki.