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

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.

Transcription Factor Myeloid Zinc-Finger 1 Suppresses Human Gastric Carcinogenesis by Interacting with Metallothionein 2A

“…embryogenesis (21,22,26). Because initial studies of the role of MZF1 in myeloid differentiation and leukemia (18,23), it has been demonstrated that the MZF1-dependent transcriptional changes occur in malignant cellular processes (24,27,28,30,(36)(37)(38)(39)(40)(41)(42)(43), and aberrant expression of MZF1 correlates with poor prognosis of several types of cancers (29,32,34,44,45). However, the contribution of MZF1 to tumorigenesis has not been fully elucidated (20).…”

“…Although several studies showed the impact of miRNAs on the capacity of MZF1 to regulate gene expression by targeting its 3 0 untranslated regions (34,39), or DNA methylation involved in genes regulated by MZF1 (41,46), the epigenetic regulation of MZF1 was not clear. Here we showed that the promotor region of MZF1 was methylated associated with hypoacetylation of histone in gastric cancer cells and primary tumor tissues, and epigenetic silencing of MZF1 expression in gastric cancer cells was reversible by treatment with epigenetic agents, or DATS.…”

The Mutational Landscape of the Oncogenic MZF1 SCAN Domain in Cancer

“…A complex and heterogeneous role of MZF1 in tumors is supported by studies in cellular and animal models of different types of cancer (Hsieh et al, 2007; Mudduluru et al, 2010; Rafn et al, 2012; Chen et al, 2014; Tsai et al, 2015; Vishwamitra et al, 2015; Nan et al, 2016). The effects mediated by MZF1 seem to be strictly dependent on the cancer type.…”

Genome-Scale Single Nucleotide Resolution Analysis of DNA Methylation in Human Autosomal Dominant Polycystic Kidney Disease

“…Methylation at the promoter of a gene is frequently associated with a loss of gene expression, while methylation in the gene body, particularly at the 3′ end of the gene, correlates with active expression of that gene [9]. There are, however, many exceptions to this generalized observation [10][11][12][13].…”