GATA-4 and GATA-5 Transcription Factor Genes and Potential Downstream Antitumor Target Genes Are Epigenetically Silenced in Colorectal and Gastric Cancer

Abstract

The GATA family of transcription factors participates in gastrointestinal (GI) development. Increases in GATA-4 and -5 expression occur in differentiation and GATA-6 expression in proliferation in embryonic and adult settings. We now show that in colorectal cancer (CRC) and gastric cancer promoter hypermethylation and transcriptional silencing are frequent for GATA-4 and -5 but are never seen for GATA-6. Potential antitumor target genes upregulated by GATA-4 and -5, the trefoil factors, inhibin␣, and disabled-2 (Dab2) are also silenced, in GI cancers, with associated methylation of the promoters. Drug or genetically induced demethylation simultaneously leads to expression, in CRC cells, of all of the GATA-4, -5, and downstream genes. Expression of exogenous GATA-5 overrides methylation at the downstream promoters to activate the target genes. Selection for silencing of both upstream transcription factors and their target genes in GI cancers could indicate that epigenetic silencing of the involved genes provides a summated contribution to tumor progression.

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

“…Collectively then, the summarised findings suggest that impairment of the HNF1b/ HNF4a signalling network may lead to tumour formation. Similar epigenetic inactivation of a critical regulator of a transcriptional network has been reported for several other genes, including estrogen receptor (Leu et al, 2004) and GATA (Akiyama et al, 2003). Epigenetic inactivation of such transcription factors may affect multiple downstream genes, causing aberrant alteration of signalling pathways involved in a wide array of cellular functions, including growth, differentiation and apoptosis.…”

DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer

“…DNA methylation was quantified at five 'type A' genes ESR1, GATA5, HIC1, HPP1 and SFRP1 (Issa et al, 1994;Young et al, 2001;Akiyama et al, 2003;Chen et al, 2004;Suzuki et al, 2004) and 10 'type C' markers MLH1, CDKN2A, MGMT, MINT2, MINT31, CACNA1G, IGF2, RUNX3, NEUROG1 and SOCS1 Issa, 2004;Shen et al, 2005Shen et al, , 2007bWeisenberger et al, 2006). Specific 'type A' genes were selected for their relevance to colorectal neoplasia and for evidence (unpublished data) that each had relatively high methylation within peritumoral 'normal' mucosa.…”

Suppression of Cellular Apoptosis Susceptibility (CSE1L) Inhibits Proliferation and Induces Apoptosis in Colorectal Cancer Cells

“…Efforts have been made to search for molecular markers and therapeutic targets to improve the early diagnosis and prognosis of colorectal patients. Several candidate genes such as VEGF (Kim et al, 2008), GATA-4 and GATA-5 (Akiyama et al, 2003), SFRP (Suzuki et al, 2004), CSE-1L and COX-2 (Eberhart et al, 1994) have been implicated in disease progression and new therapeutic approaches against these targets have potential for the treatment of colon cancers. CSE1L is the human homologue to the yeast gene CSE1.…”