ZNF498 promotes hepatocellular carcinogenesis by suppressing p53-mediated apoptosis and ferroptosis via the attenuation of p53 Ser46 phosphorylation

Abstract

Background Dysfunctional p53 signaling is one of the major causes of hepatocellular carcinoma (HCC) tumorigenesis and development, but the mechanisms underlying p53 inactivation in HCC have not been fully clarified. The role of Krüppel-associated box (KRAB)-type zinc-finger protein ZNF498 in tumorigenesis and the underlying mechanisms are poorly understood. Methods Clinical HCC samples were used to assess the association of ZNF498 expression with clinicopathological characteristics and patient outcomes. A mouse model in which HCC was induced by diethylnitrosamine (DEN) was used to explore the role of ZNF498 in HCC initiation and progression. ZNF498 overexpression and knockdown HCC cell lines were employed to examine the effects of ZNF498 on cellular proliferation, apoptosis, ferroptosis and tumor growth. Western blotting, immunoprecipitation, qPCR, luciferase assays and flow cytometry were also conducted to determine the underlying mechanisms related to ZNF498 function. Results ZNF498 was found to be highly expressed in HCC, and increased ZNF498 expression was positively correlated with advanced pathological grade and poor survival in HCC patients. Furthermore, ZNF498 promoted DEN-induced hepatocarcinogenesis and progression in mice. Mechanistically, ZNF498 directly interacted with p53 and suppressed p53 transcriptional activation by inhibiting p53 Ser46 phosphorylation. ZNF498 competed with p53INP1 for p53 binding and suppressed PKCδ- and p53INP1-mediated p53 Ser46 phosphorylation. In addition, functional assays revealed that ZNF498 promoted liver cancer cell growth in vivo and in vitro in a p53-dependent manner. Moreover, ZNF498 inhibited p53-mediated apoptosis and ferroptosis by attenuating p53 Ser46 phosphorylation. Conclusions Our results strongly suggest that ZNF498 suppresses apoptosis and ferroptosis by attenuating p53 Ser46 phosphorylation in hepatocellular carcinogenesis, revealing a novel ZNF498-PKCδ-p53INP1-p53 axis in HCC cells that would enrich the non-mutation p53-inactivating mechanisms in HCC.

The potential interplay between G-quadruplex and p53: their roles in regulation of ferroptosis in cancer

“…The complicated models are tightly involved in p53-mediated ferroptosis. Targeting p53 pathways is a promising strategy for anticancer therapy, and various inhibitors are being developed, including ZNF498 ( Zhang X. et al, 2022 ), and Eupaformosanin ( Wei et al, 2022 ).…”

Post-Translational Modifications of p53 in Ferroptosis: Novel Pharmacological Targets for Cancer Therapy

“…Phosphorylation of p53 at Ser46 has been implicated in p53 activation and its various pathophysiological effects. This type of phosphorylation induces apoptosis and ferroptosis in cells exposed to various stress ( Zhang et al, 2022 ). An example is ZNF498, one of the Krüppel-associated box domain zinc-finger proteins.…”

“…Thus, overexpression of ZNF498 is presumably associated with tumor advancement and poor prognosis in hepatocellular carcinoma. A potential underlying mechanism involves attenuated phosphorylation of p53 at Ser46, which inhibits p53-mediated apoptosis and ferroptosis ( Zhang et al, 2022 ). Another example is the Pro47Ser polymorphism (S47), which converts the proline residue adjacent to Ser46 in human p53 into serine ( Lane, 2016 ).…”

“…Several small-molecule inhibitors can block or promote the interplay between specific PTMs of p53 and corresponding upstream proteins; these inhibitors include aurora-A, ZNF498, and eupaformosanin ( Hsueh et al, 2013 ; Wei et al, 2022 ; Zhang et al, 2022 ). For example, ZNF498 inhibits Ser46 phosphorylation to reduce p53 transcription in hepatocellular carcinoma ( Zhang et al, 2022 ). This provides a novel perspective for the treatment of hepatocellular carcinoma by suppressing ZNF498.…”

Overexpression of SRD5A3 in Hepatocellular Carcinoma and Its Molecular Mechanism: A Study of Bioinformatics Exploration Analysis with Experimental Verification

“…Overall, 50% of human cancer carried p53 mutation, p53 mutation promoted multiple cancer types cell growth, survival, and metastasis to maintain the malignant behavior of cancer cells. Although single base mutation in TP53 occurs in approximately 25% of HCC [4], many literature revealed that p52 mutation is one of the most causes of HCC tumorigenesis and progression [5,6].…”