Enhancer of zeste homolog 2 downregulates E-cadherin by mediating histone H3 methylation in gastric cancer cells.
Overexpression of enhancer of zeste homolog 2 (EZH2), an epigenetic repressor, occurs in various malignancies and is associated with poor prognosis; however, the functional role of EZH2 overexpression in cancer versus non-cancerous tissue remains unclear. In this study, we found an inverse correlation between EZH2 and E-cadherin gene expression in gastric cancer cells. Knockdown of EZH2 by short interfering RNA in gastric cancer cells resulted in a restoration of the E-cadherin gene. We showed that the EZH2 complex existed with histone H3 and Lys27, which were methylated on E-cadherin promoter regions in gastric cancer cells. The restoration of E-cadherin was not involved in the change of the DNA methylation status in the E-cadherin promoter region. Immunofluorescence staining confirmed the expression of E-cadherin protein present in the cell membrane was restored after knockdown of EZH2, resulting in changing the cancer phenotype, such as its invasive capacity. In vivo, the relationship of inverse expression between EZH2 protein and E-cadherin protein was observed at the individual cellular level in gastric cancer tissue. This study provides into the mechanisms underlying the functional role of EZH2 overexpression in gastric cancer cells and a new modality of regulation of E-cadherin expression in silencing mechanisms of tumor suppressor genes. Our present study paves the way for exploring the blockade of EZH2 overexpression as a novel approach to treating cancer.
Fujii
Satoshi
S
Pathology Division, Research Center for Innovative Oncology, National Cancer Center at Kashiwa, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. aochiai@east.ncc.go.jp
Ochiai
Atsushi
A
D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006657:Histones / Q000378:metabolism*; D006801:Humans; D063151:Polycomb Repressive Complex 2; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; D004268:DNA-Binding Proteins; D006657:Histones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2