DNA methylation promotes paired box 2 expression via myeloid zinc finger 1 in endometrial cancer.

Nan Jia,Yinhua Yu,Qing Li,Weiwei Feng,Jieyu Wang,Keqin Hua,Kwong-Kwok Wong,Xiang Tao,Kaikai Chang

doi:10.18632/oncotarget.12626

Abstract

This work investigated the role of paired box 2 (PAX2) in endometrial cancer and its epigenetic regulation mechanism. Endometrial cancer tissues and cell lines exhibited increased PAX2 expression compared with hyperplasia, normal endometrium and endometrial epithelial cells. Knock-down of PAX2 resulted in reduced cell viability, invasion and migration, and PAX2 overexpression caused the opposite effects. Increased methylation of the PAX2 promoter was observed in both cancer tissues and cell lines and was positively correlated with PAX2 expression. After 5-Aza-CdR treatment, PAX2 mRNA and protein were down-regulated, and PAX2 methylation was decreased. Deletion analysis confirmed that a repressive transcriptional regulatory region of the PAX2 promoter coincided with the hypermethylated region identified in MassARRAY analysis. Binding sites of myeloid zinc finger 1 (MZF1) are predicted in the defined region. Knock-down of MZF1 up-regulated the transcriptional activity and protein level of PAX2 after 5-Aza-CdR treatment, which indicated that MZF1 may act as a repressive transcription factor when the PAX2 promoter is unmethylated. In conclusion, PAX2 is involved in the carcinogenesis of endometrial cancer by stimulating cell growth and promoting cell motility. The overexpression of PAX2 in endometrial cancer is regulated by promoter hypermethylation and the transcription factor MZF1.

Highlights

Endometrial cancer (EnCa) is one of the most common cancers of women and has an increasing incidence worldwide
Because paired box 2 (PAX2) expression was increased in endometrial cancer tissues compared with normal endometrium, we assumed that PAX2 played an oncogenic role in the carcinogenesis of endometrial cancer
PAX2 is expressed in multiple tumors, and its expression is essential for tumor cell survival in a variety of cancers, including cancers of the female reproductive tract

Summary

Introduction

Endometrial cancer (EnCa) is one of the most common cancers of women and has an increasing incidence worldwide. In addition to genetic changes, the dysregulation of genes by DNA methylation plays a significant role in tumor initiation and progression. The pathogenesis and progression of endometrial cancer related to gene dysfunction via epigenetic regulation are rarely reported. PAX2 is a biomarker of mesonephric duct-derived tumors [6], and positive expression has been reported in 67% of papillary serous ovarian cancers [7] and low-grade ovarian cancer [8, 9]. PAX2 can function as a cancer promoter or suppressor depending on the genetic background [10]. Abnormal expression of PAX2 occurs in endometrial cancer [11,12,13,14,15,16,17,18,19,20]

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Results

Conclusion