BRPF1 inhibition reduces migration and invasion of metastatic ovarian cancer cells, representing a potential therapeutic target

Abstract

Abstract Ovarian Cancer (OC) is the most lethal gynecological malignancy, characterized by peritoneal metastasis, directly linked to most OC-related deaths. Here, by interrogating CRISPR-Cas9 loss-of-function genetic screen data, we identified a list of genes essential for metastatic OC, including several well-known oncogenes (PAX8, CCNE1, WWTR1, WT1, KAT6A, MECOM, and SOX17) and others whose roles in OC have not yet been explored. Protein-protein interaction analysis of the selected genes revealed the presence of a protein network participating in the epigenetic regulation of gene expression. For one of the network components, BRPF1, we found that its increased expression correlates with OC progression and a poor prognosis for OC patients. Functional assays demonstrated that BRPF1 inhibition significantly reduces cellular migration and invasion, supporting its role in metastatic progression. Pharmacological blockade of BRPF1 using small molecule inhibitors resulted in reduced proliferation of high-grade serous OC cells through mechanisms involving the activation of programmed cell death, cell cycle deregulation, and enhanced DNA damage. Furthermore, analysis of transcriptional changes induced by BRPF1 targeting showed that the growth inhibitory effects may be mediated by the deregulation of PPARα signaling. The obtained results indicate that BRPF1 represents a novel potential therapeutic target for metastatic OC treatment.

Keywords

• Ovarian cancer
• Metastasis
• CRISPR-Cas9
• BRPF1
• Small molecule inhibitor