<scp>KRAB</scp> Zinc‐Finger Protein <scp>ZNF205</scp> Promotes Hepatocellular Carcinoma via p53 Pathway Repression

The tumor suppressor p53 is frequently dysregulated in cancer, whereas the mechanisms underlying its functional impairment remain unclear. Our previously identified KRAB domain-containing zinc finger proteins (KZFPs) as key p53 regulators in tumorigenesis and progression, specific members and their cancer-relevant mechanistic roles require further characterization. Here, we identified ZNF205, an SQ/TQ motif-bearing KZFP, as a critical oncogenic regulator in HCC. The pan-cancer analysis related to revealed that ZNF205 is an unfavorable prognostic factor for p53 wild-type patients with hepatocellular carcinoma (HCC). ZNF205 interacts with p53 and significantly inhibits its transcriptional activity by impeding the binding of p53 to target genes. Overexpression and knockdown of ZNF205 increase and decrease the malignant phenotype of HCC cells in a p53-dependent manner both in vitro and in vivo, respectively. Our study unveils ZNF205 as a novel p53 regulator and establishes its pro-tumorigenic function in HCC. These results reveal a novel p53 dysregulation mechanism in HCC and expand known KZFP-mediated p53 inactivation pathways, nominating ZNF205 as a therapeutic target to restore p53 function in HCC.