Zinc-finger protein p52-ZER6 accelerates colorectal cancer cell proliferation and tumour progression through promoting p53 ubiquitinationResearch in context
Can Huang,
Shourong Wu,
Wenfang Li,
Arin Herkilini,
Makoto Miyagishi,
Hezhao Zhao,
Vivi Kasim
Affiliations
Can Huang
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
Shourong Wu
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
Wenfang Li
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
Arin Herkilini
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
Makoto Miyagishi
Molecular Composite Medicine Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8566, Japan
Hezhao Zhao
Chongqing University Cancer Hospital, Chongqing University, Chongqing 400030, China
Vivi Kasim
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; Corresponding author at: The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
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 G0-G1 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. Keywords: p53 ubiquitination, Cell cycle, Zinc-finger protein, ZER6, p52-ZER6
