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Recent data suggest that the transcription factor Zfp148 represses activation of the tumor suppressor p53 in mice and that therapeutic targeting of the human orthologue ZNF148 could activate the p53 pathway without causing detrimental side effects. We have previously shown that  Zfp148  deficiency promotes p53-dependent proliferation arrest of mouse embryonic fibroblasts (MEFs), but the underlying mechanism is not clear. Here, we showed that  Zfp148  deficiency downregulated cell cycle genes in MEFs in a p53-dependent manner. Proliferation arrest of  Zfp148 -deficient cells required increased expression of ARF, a potent activator of the p53 pathway. Chromatin immunoprecipitation showed that Zfp148 bound to the  ARF  promoter, suggesting that Zfp148 represses  ARF  transcription. However, Zfp148 preferentially bound to promoters of other transcription factors, indicating that deletion of  Zfp148  may have pleiotropic effects that activate ARF and p53 indirectly. In line with this, we found no evidence of genetic interaction between  TP53  and  ZNF148  in CRISPR and siRNA screen data from hundreds of human cancer cell lines. We conclude that  Zfp148  deficiency, by increasing  ARF  transcription, downregulates cell cycle genes and cell proliferation in a p53-dependent manner. However, the lack of genetic interaction between  ZNF148  and  TP53  in human cancer cells suggests that therapeutic targeting of ZNF148 may not increase p53 activity in humans.

Genomic profiling of the transcription factor Zfp148 and its impact on the p53 pathway