Zinc-finger protein p52-ZER6 accelerates colorectal cancer cell proliferation and tumour progression through promoting p53 ubiquitination

Abstract

Background: Aberrant expression of p53 and its downstream gene p21 is closely related to alterations in cell cycle and cell proliferation, and is common among cancer patients. However, the underlying molecular mechanism has not been fully unravelled. ZER6 is a zinc-finger protein with two isoforms possessing different amino termini (Ntermini) in their proteins, p52-ZER6 and p71-ZER6. The biological function of ZER6 isoforms, as well as their potential involvement in tumourigenesis and the regulation of p53 remain elusive. Methods: The effect of ZER6 isoforms on p53 and p21 was determined using specific knockdown and overexpression. p52-ZER6 expression in tumours was analysed using clinical specimens, while gene modulation was used to explore p52-ZER6 roles in regulating cell proliferation and tumourigenesis. The mechanism of p52-ZER6 regulation on the p53/p21 axis was studied using molecular biology and biochemical methods. Findings: p52-ZER6 was highly expressed in tumour tissues, and was closely related with tumour progression. Mechanistically, p52-ZER6 bound to p53 through a truncated KRAB (tKRAB) domain in its N-terminus and enhanced MDM2/p53 complex integrity, leading to increased p53 ubiquitination and degradation. p52-ZER6silencing induced G 0-G 1 phase arrest, and subsequently reduced cell proliferation and tumourigenesis. Intriguingly, this regulation on p53 was specific to p52-ZER6, whereas p71-ZER6 did not affect p53 stability, most likely due to the presence of a HUB-1 domain. Interpretation: We identified p52-ZER6 as a novel oncogene that enhances MDM2/p53 complex integrity, and might be a potential target for anti-cancer therapy.

The transcriptional regulator ZNF398 mediates pluripotency and epithelial character downstream of TGF-beta in human PSCs

“…Previous studies reported that ZNF398 directly activates transcription 44 and is regulated by Oestrogen Receptor Alpha 44,55 . Two isoforms of ZNF398 have been described 44,55,56 , called p71 and p52. The shorter isoform (p52), lacks a N-terminal domain and promotes proliferation of cancer cells by ubiquitination of p53 56 .…”

“…Two isoforms of ZNF398 have been described 44,55,56 , called p71 and p52. The shorter isoform (p52), lacks a N-terminal domain and promotes proliferation of cancer cells by ubiquitination of p53 56 . In hPSCs the longer isoform (p71) is predominant and has been used in all our experiments.…”

DUF3669, a “domain of unknown function” within ZNF746 and ZNF777, oligomerizes and contributes to transcriptional repression

“…It is important to bear this in mind when considering the role of ZNF746 in a certain biological context like in Parkinson’s disease [35]. Intriguingly, a very recent report illustrated isoform-dependent functions for ZNF398 on a posttranslational level: Only the isoform lacking amino-terminal sequences including DUF3669 and a major part of KRAB-A formed a complex with tumor suppressor TP53 and MDM2 and thus enhanced ubiquitinylation and subsequent degradation of TP53 [54].…”

KRAB-ZFP Transcriptional Regulators Acting as Oncogenes and Tumor Suppressors: An Overview

“…ZER6, known as well as ZNF398, has two main isoforms: P52-ZER6 and P71-ZER6 [ 110 ]. The p52-ZER6 isoform has high expression in colorectal cancer ( Figure 4 ), which coincides with disease progression [ 111 ]. Huang and colleagues provided evidence that p52-ZER6 (but not p71-ZER6) enhances the interaction between p53 and MDM2, which in turn augments p53 ubiquitination and degradation.…”

“…ZER6 knockdown resulted in the increased expression of the p53 target, namely p21 ( Figure 6 B), which negatively regulates the cell cycle ( Figure 5 ). This further hindered cell proliferation in human colon carcinoma cell line HCT116 [ 111 ]. High p52-ZER6 expression was also detected in ER-positive breast cancer cell lines.…”