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, Kazuo Asanoma, Tomoka Takao, Kiyoko Kato, Norio Wake

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 HOP promoter, which leads to HEC development.

Original languageEnglish
Pages (from-to)2577-2588
Number of pages12
JournalInternational Journal of Cancer
Volume124
Issue number11
DOIs
Publication statusPublished - Jun 1 2009

Keywords

  • 17β-estradiol
  • DNA methylation
  • HOPX
  • Human uterine endometrial cancer
  • Serum response factor
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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