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Molecular and Cellular Biology, December 2003, p. 8429-8439, Vol. 23, No. 23
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.23.8429-8439.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Yoshimitsu Akiyama,1 Neil Watkins,1 Hiromu Suzuki,1 Kam-Wing Jair,1 Manon van Engeland,1,3 Manel Esteller,1,4 Hidekazu Sakai,2 Chun-Yan Ren,2 Yasuhito Yuasa,2 James G. Herman,1 and Stephen B. Baylin1*

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231,1 Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan,2 Department of Pathology, University Maastricht, 6200 MD Maastricht, The Netherlands,3 Cancer Epigenetics Laboratory, Spanish National Cancer Center, 28029 Madrid, Spain4

Received 1 July 2003/ Accepted 15 August 2003

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{alpha}, 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.

* Corresponding author. Mailing address: Bunting-Blaustein Cancer Research Building, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans St., Baltimore, MD 21231. Phone: (410) 955-8506. Fax: (410) 614-9884. E-mail: sbaylin{at}jhmi.edu.

Molecular and Cellular Biology, December 2003, p. 8429-8439, Vol. 23, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.23.8429-8439.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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