MYC Targeted Rad50 Drives Progression of High-Grade Serous Ovarian Cancer via NF-κB Activation

Background: Rad50 is a component of MRN complex, which consists of Mre11-Rad50-Nbs1. The MRN complex participates in DNA double-strand break repair and DNA-damage checkpoint activation. We sought to investigate the clinical and functional significance of Rad50 in high-grade serous ovarian cancer. MethodsChromatin immunoprecipitation and luciferase assays were performed to evaluate the regulatory roles of MYC on Rad50 expression. Association between Rad50 expression and clinical outcome in HGSOCs was evaluated by Kaplan-Meier analysis. Invasion, clonogenic assay and xenograft mice model were conducted to determine to functional role of Rad50 in ovarian cancer. Protein immunoprecipitation and immunofluorescence were used to explore the underlying mechanisms. ResultsMYC proto-oncogene transcriptionally activated Rad50 expression in high-grade serous ovarian cancer. Next, we provided evidences that Rad50 was frequently upregulated in HGSOCs and enhanced Rad50 expression inversely correlated with patient’s survival. In addition, ectopic expression of Rad50 promoted proliferation/invasion and induced EMT of ovarian cancer cells, whereas knockdown of Rad50 led to decreased aggressive behaviors. Mechanistic investigations revealed that Rad50 induced aggressiveness in HGSOC via activation NF-κB signaling pathway. Moreover, we identified CARD9 as an interacting protein of Rad50 in ovarian cancer cells and activation of NF-κB pathway by Rad50 is CARD9 dependent. ConclusionsOur findings provide evidence that MYC targeted Rad50 exhibits oncogenic property via NF-κB activation in high-grade serous ovarian cancer.