The first two authors contributed equally to this work.
Cancer Cell Biology
Homeobox gene HOPX is epigenetically silenced in human uterine endometrial cancer and suppresses estrogen-stimulated proliferation of cancer cells by inhibiting serum response factor
Article first published online: 15 DEC 2008
Copyright © 2008 Wiley-Liss, Inc.
International Journal of Cancer
Volume 124, Issue 11, pages 2577–2588, 1 June 2009
How to Cite
Yamaguchi, S., Asanoma, K., Takao, T., Kato, K. and Wake, N. (2009), Homeobox gene HOPX is epigenetically silenced in human uterine endometrial cancer and suppresses estrogen-stimulated proliferation of cancer cells by inhibiting serum response factor. Int. J. Cancer, 124: 2577–2588. doi: 10.1002/ijc.24217
- Issue published online: 25 MAR 2009
- Article first published online: 15 DEC 2008
- Accepted manuscript online: 15 DEC 2008 12:00AM EST
- Manuscript Accepted: 2 DEC 2008
- Manuscript Received: 7 JUL 2008
- Ministry of Education, Science and Culture, Japan (Grant-in-Aid for Scientific Research). Grant Numbers: 18659489, 19791154
- human uterine endometrial cancer;
- DNA methylation;
- tumor suppressor gene;
- serum response factor
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.