Objectives The objective of this study is to improve our understanding about PARP1 in ovarian cancer stem cells (OCSCs), which would be helpful for extension of the potential of PARP inhibitors as anti-cancer drugs.
Methods SK-OV3, primary ovarian cancer cells and xenograft mice were used in the study. Genetic manipulation was performed by lentivirus systems. The stemness of OCSCs was examined by determination of sphere-forming capacities, the frequency of sphere-forming and tumor-initiating cells and the expression levels of OCSCs markers. Immunoprecipitation assay was used for determination of the binding between PARP1 and nuclear YAP. The post-translational modification of YAP was examined by western blot.
Results PARP1 positively regulates the stemness of OCSCs; treatment with PARP1 inhibitors also suppressed the stemness of OCSCs. PARP1 enhanced YAP activity reflected by upregulation of the mRNA levels of YAP target genes and the protein level of nuclear YAP. PARP1 enhanced the stabilization of YAP in nucleus and the ubiquitination of nuclear YAP was involved in this process. The positive correlation between PARP1 and nuclear YAP was found in both cell-based and mice models. Knockdown of YAP abolished the effect of PARP1 on OCSCs stemness.
Conclusions PARP1 promotes the stemness of OCSCs and stabilization of nuclear YAP is the underlying mechanism. This finding is useful for extension the clinical use of PARP1 inhibitors for eradicating human OCSCs.
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