Role of KLF5 in enhancing ovarian cancer stemness and PARPi resistance: mechanisms and therapeutic targeting.

ABSTRACT:

Background

Ovarian cancer (OC) often presents at advanced stages with poor prognosis. Although poly(ADP-ribose) polymerase inhibitors (PARPi) offer clinical benefits, resistance remains a major challenge. This study investigates the role of KLF5 in regulating OC cell stemness and contributing to PARPi resistance.

Methods

Gene expression analysis was conducted on OC cell lines and their PARPi-resistant counterparts. qRT-PCR and Western blotting assessed the expression levels of stemness markers and KLF5. IHC evaluated KLF5 expression in ovarian cancer tissue samples. Sphere formation and ALDH activity assays were used to evaluate stemness. Chromatin immunoprecipitation (ChIP) investigated KLF5's binding to the Vimentin promoter. The effects of the KLF5 inhibitor ML264 were tested in vitro using cell viability and apoptosis assays, and in vivo using a xenograft mouse model to evaluate tumor growth and response to PARPi treatment.

Results

PARPi-resistant OC cells showed elevated stemness, indicated by increased SOX2, KLF4, Nanog, and OCT4 expression. KLF5 was significantly upregulated in these cells and linked to poor clinical outcomes. PARPi-resistant cells formed larger and more numerous spheres and had higher ALDH activity. KLF5 bound to the Vimentin promoter, upregulating its expression. Inhibition of KLF5 with ML264 reduced stemness features, decreased Vimentin expression, and resensitized resistant cells to PARPi. In vivo, ML264-treated mice with PARPi-resistant tumors exhibited reduced tumor growth and increased sensitivity to PARPi.

Conclusion

KLF5 enhances stemness and contributes to PARPi resistance in ovarian cancer through Vimentin regulation. Targeting KLF5 offers a promising therapeutic strategy to overcome resistance and improve patient outcomes.

SUBMITTER: Xiao H 

PROVIDER: S-EPMC12042437 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature