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

SIMPLE SUMMARY: Cancer is among the leading causes of deaths in the US and worldwide. Although extensive research has led to a decline in the overall cancer deaths in the US since the early 1990s, cancer still remains a major cause of mortality in the US. The tumor suppressor p53 is the most frequently mutated gene in all human cancers, accounting for a loss of function in more than 50% of all human cancers. Even after years of extensive research on p53, most of the pathways regulating the p53 family network are yet to be elucidated. Here, we identified a mutual regulation between p53 and ZFP14, a member of the largest family of transcription factors in humans, whose functions have been unknown till now. We showed that p53 can increase the amount of ZFP14 when cells are under stress and that ZFP14, in turn, negatively affects the p53 protein levels forming a feedback loop. We also showed that ZFP14 carries this out as part of a complex containing the major p53 negative regulator, MDM2. Moreover, the removal of ZFP14 from cancer cells reduces their tumorigenic properties in a manner dependent on p53 levels. Our findings reveal that ZFP14 might play an important role in tumor suppression via p53. 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.