S100A4 hypomethylation affects epithelial-mesenchymal transition partially induced by LMP2A in nasopharyngeal carcinoma

Abstract

To identify cellular target genes involved in NPC cell invasion and metastasis, gene expression profiles of CNE-1 cells with or without ectopic LMP2A expression were compared by using the metastatic gene array. S100 calcium binding protein A4 (S100A4) was the highest increased one among these genes both in mRNA and protein levels of NPC cells. Moreover, S100A4 was upregulated in LMP2A-positive NPC tissues. We found that CNE-1-S100A4 showed significantly increased invasion ability as compared to the controls both in vitro and in vivo, which indicated that S100A4 induced EMT occurrence and promoted metastasis. Notably, the DNA hypomethylation of S100A4 was found in LMP2A-positive NPC tissues. Besides, inhibition of DNA methyltransferases via 5-Aza-dC stimulated the expression of S100A4 in the cells without ectopic LMP2A expression. The methylation changes were confirmed by methylation specific PCR (MSP), suggesting that LMP2A ectopic expression led to the demethylation of S100A4 promoter. These results demonstrated that LMP2A-induced hypomethylation participated in regulating S100A4 expression in NPC. Our findings provide an evidence for the emerging notion that hypomethylation and activation of correlated genes are crucial for metastasis progression in cancer. © 2015 Wiley Periodicals, Inc.

Increased S100A15 expression and decreased DNA methylation of its gene promoter are involved in high metastasis potential and poor outcome of lung adenocarcinoma

“…Moreover, we verified this phenomenon in lung adenocarcinoma cell lines with high versus low metastasis properties. In line with our findings, DNA hypomethylation and enhanced gene expression of S100A4 can increase invasive ability and promote metastasis in nasopharyngeal, laryngeal, and endometrial carcinoma [ 12 , 15 , 16 ]. Likewise, increased S100A6 expression and its DNA hypomethylation are associated with poor prognosis in gastric cancer [ 13 ].…”

“…Recently, several S100A family members have been recognized as a critical regulator of the metastatic process and epithelial-mesenchymal transition occurrence in several human cancers. Among them, S100A4 and S100A6 have been reported to be epigenetically up-regulated in nasopharyngeal and gastric cancer by DNA hypomethylation over their gene promoter regions, while S100A2 and S100A10 down-regulated in head/neck and pituitary cancer by DNA hypermethylation [ 12 , 13 ]. Our data provide evidence that S100A15 aggravates metastatic progressing in lung adenocarcinoma in vivo and in vitro through DNA hypomethylation over its gene promoter region, and CTNNB1-centered down-stream mediators.…”

Epigenetic silencing of miR-520c leads to induced S100A4 expression and its mediated colorectal cancer progression

“…With this line of evidence, we intrasplenically injected HCT116 cells stably overexpressing miR-520c-3p in SCID beige mice and observed slightly reduced metastasis formation in the liver compared to the control-miR group. With this results, one can speculate that especially in this context the downregulation of miR-520c-3p due to a hypermethylation of its regulatory region could be one of the mechanisms for S100A4 overexpression in different cancer entities, apart from its previously described epigenetic and Wnt/β-catenin mediated transcriptional regulation [14, 58]. …”

Mutual regulation of microRNAs and DNA methylation in human cancers

“…For example, S100 calcium binding protein A4 (S100A4) induces EMT and promotes metastasis and was reported to be hypomethylated and upregulated in LMP2A-positive NPC tissues. 76 Another study reported that the synergistic hypomethylation of Jagged1 and Notch1 genes was involved in the metastasis of breast cancer. 77 In addition, Iroquois homeobox 1 (IRX1) hypomethylation is a potential molecular marker for lung metastasis.…”