The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China; The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China; State and Local Joint Engineering Laboratory for Vascular Implants, Chongqing 400044, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei 230032, China.
The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China; The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China; State and Local Joint Engineering Laboratory for Vascular Implants, Chongqing 400044, China.
EBioMedicine. 2019 Oct;48:248-263. doi: 10.1016/j.ebiom.2019.08.070. Epub 2019 Sep 11.
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.
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.
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-G 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.
We identified p52-ZER6 as a novel oncogene that enhances MDM2/p53 complex integrity, and might be a potential target for anti-cancer therapy.
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，在癌症患者中较为常见。然而，其潜在的分子机制尚未完全阐明。ZER6 是一种具有两个不同氨基末端（N 末端）的锌指蛋白异构体的锌指蛋白，p52-ZER6 和 p71-ZER6。ZER6 异构体的生物学功能，以及它们在肿瘤发生和 p53 调节中的潜在作用仍不清楚。
使用特定的敲低和过表达来确定 ZER6 异构体对 p53 和 p21 的影响。使用临床标本分析肿瘤中的 p52-ZER6 表达，同时通过基因调节来探索 p52-ZER6 在调节细胞增殖和肿瘤发生中的作用。使用分子生物学和生化方法研究 p52-ZER6 对 p53/p21 轴的调节机制。
p52-ZER6 在肿瘤组织中高表达，与肿瘤进展密切相关。在机制上，p52-ZER6 通过其 N 端的截断 KRAB（tKRAB）结构域与 p53 结合，并增强了 MDM2/p53 复合物的完整性，导致 p53 泛素化和降解增加。p52-ZER6 沉默诱导 G1-G0 期阻滞，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，这可能是由于存在 HUB-1 结构域。
我们确定 p52-ZER6 是一种增强 MDM2/p53 复合物完整性的新型癌基因，可能是抗癌治疗的潜在靶点。
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