ZNF655 promotes tumor growth and chemoresistance by targeting MAFF-CCND1 axis in ovarian cancer.

Abstract

Ovarian cancer (OC) has the highest mortality rate among gynecological malignancies. The role of zinc finger protein 655 (ZNF655) in cancer progression has been highlighted but remains unclear and needs further exploration. In this study, our findings revealed that ZNF655 is aberrantly upregulated in OC. Depletion of ZNF655 inhibited the malignant behaviors of OC, manifested by attenuated proliferation, promoted apoptosis, inhibited migration and reduced stem cell properties. Mechanistically, ZNF655 facilitated nuclear translocation of MAFF transcription factor in OC cells, leading to MAFF's direct binding to the promoter of CCND1 and subsequent transcriptional activation of CCND1. Subsequent rescue experiments demonstrated that CCND1 plays a critical role in mediating ZFN655-dependent proliferation and stemness maintenance. Notably, ZNF655 overexpression conferred paclitaxel resistance in OC cells, suggesting clinical implications for chemoresistance. These in vitro findings were corroborated by murine xenograft models, where ZNF655-overexpressing tumors exhibited accelerated growth kinetics and elevated Ki-67 indices. Importantly, clinical correlation analysis of OC specimens revealed that ZNF655 overexpression correlated with poor patient outcome in OC. In conclusion, these results not only advance the understanding of the molecular mechanisms underlying OC progression but also identify ZNF655 as a potential preclinical therapeutic target for OC treatment.