Abstract 200: Methylation of GATA4 and GATA5 transcription factor genes in gastric cancers

Abstract

Abstract GATA factors comprise a small family of transcription regulatory proteins containing two conserved zinc finger DNA binding domains for the consensus sequence (WGATAR). Among the six GATA factors, GATA-1/2/3 factors are prominently expressed in the hematopoietic cell lineage, while GATA-4/5/6 factors show a partly overlapping expression pattern in the heart and endoderm-derived organs. We previously reported that GATA4 and GATA5 were silenced by their promoter hypermethylation in gastrointestinal, lung and ovarian cancers. However, it remains unknown the mechanism underlying loss of GATA transcription factors in gastric carcinogenesis. To clarify the role of GATA, we examined GATA4/5 methylation and their downstream target genes in gastric cancer (GC). By using methylation specific PCR, the methylation frequency of GATA5 (30, 39%) was significantly higher than that of GATA4 (10, 13%) in 77 GC tissues (P<0.01). However, methylation of GATA6 was not observed in GCs examined. We transiently over-expressed GATA4 or GATA5 in GC cell lines lacking their expression by aberrant methylation. Both GATA4 and GATA5 suppressed colony formation and cell proliferation in MKN74 cells. After GATA4/5 over-expression in MKN74 and KATO-III cells, enhanced expression of numerous genes including ones indicating tumor-suppressive functions, such as TFF1, disabled-2 and IQGAP2, was observed by microarray and RT-PCR analyses. The target genes of GATA4 and GATA5 were closely similar in MKN74 cells. We also preformed siRNA transfection of GATA4 and GATA5 in AGS and HSC43 cells which basally expressed them. Reduced expression of above predicted GATA target genes was detected in these two cell lines after siRNA transfection. These data suggest that loss of GATA4 and GATA5 expression may contribute to gastric carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 200.