C/EBPβ Promotes PARP Inhibitor Resistance By Enhancing Homologous Recombination Repair In Ovarian Cancer

Background: Poly-(ADP ribose)-polymerase(PARP)inhibitors are efficacious in treating ovarian cancer with homologous recombination deficiency(HRD).However,in homologous recombination-proficient cancers,they exhibit suboptimal efficiency owing to the insufficiency in inducing synthetic lethality.Methods: The reciprocal relationship between C/EBPβ and PARP inhibitor resistance was explored in vitro and in vivo.To clarify the effects of C/EBPβ expression on PARP inhibitor responsiveness,PARP inhibitor-resistant cell strain,primary cultures of ovarian cancer tissues,and paired specimens of ovarian cancers before and after olaparib treatment were used.Gene expression was measured by immunoblotting,immunohistochemical staining,RNA-sequencing,and RT-q PCR.To profile C/EBPβ targets,chromatin immunoprecipitation and promoter luciferase reporter assays were performed.The effects of C/EBPβ on DNA damage repair were assessed by HR reporter assays,immunofluorescence,and comet assays.Results: C/EBPβ affected DNA damage repair signals in ovarian cancer.C/EBPβ expression was inversely correlated with PARP inhibitor sensitivity in homologous recombination-proficient ovarian cancer cell lines and ovarian cancer tissues.High C/EBPβ expression enhanced PARP inhibitor tolerance in ovarian cancer,and PARP inhibitor treatment in turn induced C/EBPβ expression.C/EBPβ directly targeted and upregulated multiple genes of the homologous recombination pathway(including BRCA1,BRIP1,BRIT1,and RAD51),thereby inducing upregulation of homologous recombination capacity and mediating acquired PARP inhibitor resistance of ovarian cancer.Effects of C/EBPβ were abolished by gene interference of the homologous recombination pathway.Conclusion: C/EBPβ promotes PARP inhibitor resistance in ovarian cancer;it is a key regulator of the homologous recombination pathway and an indicator of PARP inhibitor responsiveness.Targeting C/EBPβ could induce HRD and rescue PARP inhibitor sensitivity accordingly,which shows promise for tracking PARP inhibitor responsiveness during treatment and extending the benefits of PARP inhibitors to homologous recombination-proficient ovarian cancer patients.