Human ZNF312b oncogene is regulated by Sp1 binding to its promoter region through DNA demethylation and histone acetylation in gastric cancer

Abstract

In a previous study, human ZNF312b was identified as a cell proliferation-associated oncogene via the K-ras/extracellular signal-regulated kinase cascade in gastric cancer. However, the mechanism concerning its transcriptional activation remains unknown. Here, we show that DNA methylation and histone acetylation of the ZNF312b promoter function as a switch for ZNF312b transcriptional activation in gastric cancer. The transcription level of ZNF312b was increased by treatment with a demethylating agent, 5-aza-2 0 -deoxycytidine and the histone deacetylase inhibitor sodium butyrate, in several human cancer cell lines including gastric cancer. Consistent with these results, epigenetic analysis, such as pyrosequencing, bisulfate sequencing and methyl-specific polymerase chain reaction (MSP), showed that the expression level of ZNF312b is highly dependent on the degree of DNA methylation in gastric cancer cell lines. In addition, by ChIP assay using anti-acetyl/methyl H3K9 antibodies, histone acetylation was shown to mediate the expression of the ZNF312b gene. Interestingly, ChIP assay using the Sp1 antibody revealed that the binding of transcription factor Sp1 to the ZNF312b promoter for its transcriptional activation requires DNA demethylation and histone acetylation. Moreover, a knockdown of Sp1 resulted in a decrease in ERKmediated proliferation via downregulation of the ZNF312b gene in gastric cancer cells. Taken together, these results suggest that the aberrant expression of ZNF312b promotes gastric tumorigenesis through epigenetic modification of its promoter region and provides a molecular mechanism for ZNF312b expression to contribute to the progression of gastric cancer.

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“…These assays were performed as described previously 11 . Detailed methods are provided in the Supplemental Information.…”

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“…The reduction of p21 has been validated to be caused by hypoacetylation of histone H3 [72]. By contrast, hyperacetylation in H3 of ZNF312b (FEZ family zinc finger 1) promotes the progression of gastric cancer [73]. Reduced histone H4 acetylation was found in some gastric lesions exhibiting intestinal metaplasia and has been shown to correlate with advanced tumor stage, invasion, and lymph node metastasis in gastric patients [74, 75].…”