Homeobox gene HOPX is epigenetically silenced in human uterine endometrial cancer and suppresses estrogen-stimulated proliferation of cancer cells by inhibiting serum response factor
Shinichiro Yamaguchi
Department of Obstetrics and Gynecology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
The first two authors contributed equally to this work.
Search for more papers by this authorCorresponding Author
Kazuo Asanoma
Division of Molecular and Cell Therapeutics, Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
The first two authors contributed equally to this work.
Fax: 1-913-588-8287
Institute of Maternal-Fetal Biology, Division of Cancer and Developmental Biology, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USASearch for more papers by this authorTomoka Takao
Department of Obstetrics and Gynecology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
Search for more papers by this authorKiyoko Kato
Division of Molecular and Cell Therapeutics, Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
Search for more papers by this authorNorio Wake
Department of Obstetrics and Gynecology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
Search for more papers by this authorShinichiro Yamaguchi
Department of Obstetrics and Gynecology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
The first two authors contributed equally to this work.
Search for more papers by this authorCorresponding Author
Kazuo Asanoma
Division of Molecular and Cell Therapeutics, Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
The first two authors contributed equally to this work.
Fax: 1-913-588-8287
Institute of Maternal-Fetal Biology, Division of Cancer and Developmental Biology, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USASearch for more papers by this authorTomoka Takao
Department of Obstetrics and Gynecology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
Search for more papers by this authorKiyoko Kato
Division of Molecular and Cell Therapeutics, Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
Search for more papers by this authorNorio Wake
Department of Obstetrics and Gynecology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
Search for more papers by this authorFax: 1-913-588-8287
Abstract
HOPX (homeodomain only protein X) is a newly identified homeobox gene whose loss of expression has been reported for several types of neoplasm. Although we found most human uterine endometrial cancers (HEC) defective in HOPX expression, genetic mutations in the HOPX gene were undetectable. As is the case with several tumor suppressor genes, the promoter region of HOPX is densely methylated in HEC tissue samples obtained by laser capture microdissection. HOPX mRNA and protein levels were reduced in the majority of samples, and this correlated with hypermethylation of the HOPX promoter. Forced expression of HOPX resulted in a partial block in cell proliferation, in vivo tumorigenicity and c-fos gene expression in HEC and MCF7 cells in response to 17β-estradiol (E2) stimulation. Analysis of the serum response element (SRE) of c-fos gene promoter showed that the effect of HOPX expression is associated with inhibition of E2-induced c-fos activation through the serum response factor (SRF) motif. Knockdown of HOPX in immortalized human endometrial cells resulted in accelerated proliferation. Our study indicates that transcriptional silencing of HOPX results from hypermethylation of the HOPpromoter, which leads to HEC development. © 2008 Wiley-Liss, Inc.
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