title: 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'-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 ERK-mediated 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.
authors.affiliation: Medical Genome Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors.forename: In-Sung
authors.initials: IS
authors.lastname: Song
authors.forename: Ga-Hee
authors.initials: GH
authors.lastname: Ha
authors.forename: Jeong-Min
authors.initials: JM
authors.lastname: Kim
authors.forename: So-Young
authors.initials: SY
authors.lastname: Jeong
authors.forename: Han-Chul
authors.initials: HC
authors.lastname: Lee
authors.forename: Yong Sung
authors.initials: YS
authors.lastname: Kim
authors.forename: Yung-Jin
authors.initials: YJ
authors.lastname: Kim
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
authors.forename: Nam-Soon
authors.initials: NS
authors.lastname: Kim
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D023061:Gene Order; D006657:Histones / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: C557090:FEZF2 protein, human; D006657:Histones; D016329:Sp1 Transcription Factor; D014157:Transcription Factors