The human kallikrein 10 promoter contains a functional retinoid response element.
Human kallikrein 10 (hK10) protein is expressed in normal breast but is significantly downregulated in a majority of invasive breast cancers. Thus, understanding how hK10 expression is regulated is of substantial significance. In this study, we analyzed the promoter region of hK10 using a website software (TRANSFAC 3.0), which predicted three possible retinoic acid response elements (RAREs), RARE1 at -1041 (TGACCTCGTGATCC), RARE2 at -859 (TGACCTCCTATGA) and RARE3 at -765 (TGACCTCCTGTGA), each with a half-site of a canonical sequence (TGACCT; reverse complement AGGTCA). Using electrophoretic mobility shift assays and nucleotide competition analysis, as well as chromatin immunoprecipitation of the native hK10 promoter, we demonstrated specific binding of RXR only to RARE1. The functional importance of RARE in the hK10 promoter was demonstrated by retinoid induction of hk10 promoter-reporters; furthermore, mutation of RARE1 but not of RARE2 or RARE3 abolished the induction of the reporter. Finally, we demonstrated the induction of hK10 mRNA and protein expression upon retinoid treatment of cells. In view of the correlation of the downregulation of hK10 mRNA and protein with breast cancer progression, these findings suggest a potential approach to restore hK10 expression in cancer patients.
Zeng
Musheng
M
Department of Radiation Oncology, New England Medical Center, Tufts University School of Medicine, 750 Washington Street, Boston, MA 02111, USA.
Zhang
Ying
Y
Bhat
Ishfaq
I
Wazer
David E
DE
Band
Hamid
H
Band
Vimla
V
D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007610:Kallikreins / Q000235:genetics*; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D011401:Promoter Regions, Genetic; D020218:Response Elements; D047488:Retinoid X Receptors / Q000378:metabolism; D012176:Retinoids / Q000235:genetics* / Q000494:pharmacology
D047488:Retinoid X Receptors; D012176:Retinoids; C100936:KLK10 protein, human; D007610:Kallikreins