GATA-4 and GATA-5 transcription factor genes and potential downstream antitumor target genes are epigenetically silenced in colorectal and gastric cancer.
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, inhibinalpha, 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.
Akiyama
Yoshimitsu
Y
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
Watkins
Neil
N
Suzuki
Hiromu
H
Jair
Kam-Wing
KW
van Engeland
Manon
M
Esteller
Manel
M
Sakai
Hidekazu
H
Ren
Chun-Yan
CY
Yuasa
Yasuhito
Y
Herman
James G
JG
Baylin
Stephen B
SB
D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D044127:Epigenesis, Genetic; D050991:GATA4 Transcription Factor; D050992:GATA5 Transcription Factor; D050993:GATA6 Transcription Factor; D020868:Gene Silencing; D006801:Humans; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000209:etiology / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D050992:GATA5 Transcription Factor; C494755:GATA5 protein, human; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D014157:Transcription Factors