ZFP14 Regulates Cancer Cell Growth and Migration by Modulating p53 Protein Stability as Part of the MDM2 E3 Ubiquitin Ligase Complex

Abstract

Multi-zinc finger proteins that contain a KRAB domain are part of the biggest family of transcription factors in mammals. However, the physiological or pathological functions for the majority of them are unknown. Here, we showed that ZFP14 (also known as ZNF531) is a p53 target gene that can be induced upon genotoxic stress in a p53-dependent manner. To determine the function of ZFP14 in mouse and human cancer cell lines, we generated multiple cell lines where ZFP14 was knocked out. We showed that ZFP14-KO inhibits cancer cell growth and migration. We also showed that, as a target of p53, ZFP14, in turn, represses p53 expression and that the knockdown of p53 restores the potential of ZFP14-KO cells to proliferate and migrate. Mechanistically, we found that ZFP14 modulates p53 protein stability by increasing its ubiquitination via associating with and possibly enhancing MDM2/p53 complex integrity through its zinc finger domains. Our findings suggest that the reciprocal regulation of p53 and ZFP14 represents a novel p53-ZFP14 regulatory loop and that ZFP14 plays a role in p53-dependent tumor suppression.