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Reciprocal Role Of DNA Methylation And Sp1 Binding In Ki-67 Gene Transcription

Authors Li LT, Wang X, Zhu WT, Qian GW, Pei DS, Zheng JN

Received 28 April 2019

Accepted for publication 16 October 2019

Published 18 November 2019 Volume 2019:11 Pages 9749—9759

DOI https://doi.org/10.2147/CMAR.S213769

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Melinda Thomas

Peer reviewer comments 2

Editor who approved publication: Dr Teng


Lian-Tao Li,1–3,* Xun Wang,4,* Wen-Tao Zhu,5,* Guo-Wei Qian,6 Dong-Sheng Pei,1,5 Jun-Nian Zheng1,2

1Cancer Institute, Xuzhou Medical University, Xuzhou 221000, People’s Republic of China; 2Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People’s Republic of China; 3Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People’s Republic of China; 4Department of Interventional Radiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People’s Republic of China; 5Department of Pathology, Xuzhou Medical University, Xuzhou 221000, People’s Republic of China; 6Department of Medical Oncology, Shanghai Sixth People’s Hospital, Shanghai 200000, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Dong-Sheng Pei; Jun-Nian Zheng 84 West Huaihai Road, Xuzhou, Jiangsu, People’s Republic of China
Tel +8605168558230
Email dspei@xzhmu.edu.cn; jnzheng@xzhmu.edu.cn

Purpose: DNA methylation plays major regulatory roles in gene transcription. Our previous studies confirmed that Ki-67 promoter is hypomethylated and Sp1 is a transcriptional activator of Ki-67 gene in cancer cells. However, whether Sp1-mediated transcriptional activation of Ki-67 is related to its methylation has not been studied yet.
Materials and methods: In this study, we confirmed that methylated CpG binding protein 2 (MBD2) binding to methylated DNA hindered the binding of Sp1 to Ki-67 promoter and then repressed Ki-67 transcription through chromatin immunoprecipitation (ChIP) and quantitative real-time PCR (qRT-PCR). Co-immunoprecipitation (Co-IP), ChIP, methylation-specific PCR (MS-PCR) and Western blot were utilized to analyze the effects of Sp1 binding to Ki-67 promoter on its methylation status.
Results: Less DNA methyltransferase 1 (DNMT1) bound to the Ki-67 promoter in MKN45 cells than in HK-2 cells. Histone acetyltransferase p300 that was recruited by Sp1 to Ki-67 promoter could attenuate the methylation level of Ki-67 promoter. Furthermore, higher expression of Sp1 and Ki-67 was related to the overall survival (OS), first progression (FP) and post-progression survival (PPS) in gastric cancer by scrutinizing bioinformatics datasets.
Conclusion: Taken together, our findings suggested that hypomethylation of Ki-67 promoter enhanced the binding of Sp1, which in turn maintained hypomethylation of promoter, leading to increase Ki-67 expression in cancer cells. Sp1 and Ki-67 could act promising prognostic biomarkers for clinical diagnosis and treatment of cancer.

Keywords: methylation, Ki-67, Sp1, promoter, cancer
 

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