Homeobox gene HOPX is epigenetically silenced in human uterine endometrial cancer and suppresses estrogen-stimulated proliferation of cancer cells by inhibiting 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 17beta-estradiol (E(2)) 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 E(2)-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.
Yamaguchi
Shinichiro
S
Department of Obstetrics and Gynecology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Asanoma
Kazuo
K
Takao
Tomoka
T
Kato
Kiyoko
K
Wake
Norio
N
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D044127:Epigenesis, Genetic; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D006801:Humans; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D026362:Serum Response Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology
C476884:HOPX protein, human; D018398:Homeodomain Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D026362:Serum Response Factor; D025521:Tumor Suppressor Proteins; D004958:Estradiol