Zinc-finger protein p52-ZER6 accelerates colorectal cancer cell proliferation and tumour progression through promoting p53 ubiquitination
Zinc-finger protein p52-ZER6 accelerates colorectal cancer cell proliferation and tumour progression through promoting p53 ubiquitination
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锌指蛋白p52-ZER6通过促进p53泛素化加速结直肠癌细胞增殖和肿瘤进展
DOI：
10.1016/j.ebiom.2019.08.070
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发表时间：
2019-10-01
期刊：
影响因子：
11.1
通讯作者：
Kasim, Vivi
中科院分区：
文献类型：
--
作者：
Huang, Can;Wu, Shourong;Kasim, Vivi
背景：p53及其下游基因p21的异常表达与细胞周期和细胞增殖的改变密切相关，并且在癌症患者中很常见。然而，潜在的分子机制尚未完全阐明。 ZER6 是一种锌指蛋白，有两种同工型（p52-ZER6 和 p71-ZER6）在其蛋白质中具有不同的氨基末端（N 末端）。 ZER6 亚型的生物学功能以及它们在肿瘤发生和 p53 调节中的潜在参与仍然难以捉摸。方法：使用特异性敲低和过表达来确定 ZER6 亚型对 p53 和 p21 的影响。利用临床标本分析肿瘤中 p52-ZER6 的表达，同时利用基因调制探索 p52-ZER6 在调节细胞增殖和肿瘤发生中的作用。采用分子生物学和生化方法研究了p52-ZER6对p53/p21轴的调控机制。结果显示：p52-ZER6在肿瘤组织中高表达，且与肿瘤进展密切相关。从机制上讲，p52-ZER6 通过 N 端截短的 KRAB (tKRAB) 结构域与 p53 结合，增强了 MDM2/p53 复合体的完整性，从而导致 p53 泛素化和降解增加。 p52-ZER6 沉默诱导 G(0)-G(1) 期停滞，随后减少细胞增殖和肿瘤发生。有趣的是，这种对 p53 的调节是 p52-ZER6 特有的，而 p71-ZER6 并不影响 p53 的稳定性，这很可能是由于 HUB-1 结构域的存在。 解释：我们确定 p52-ZER6 是一种新型癌基因，可以增强 MDM2/p53 复合体的完整性，并且可能是抗癌治疗的潜在靶点。 (C) 2019 年作者。由 Elsevier B.V. 出版
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 (N-termini) 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-ZER6-silencing 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. (C) 2019 The Authors. Published by Elsevier B.V.