Klf10 induces cell apoptosis through modulation of BI-1 expression and Ca2+ homeostasis in estrogen-responding adenocarcinoma cells.
Estrogen stimulates cell growth and inhibits apoptosis through estrogen receptor-mediated mechanisms in many cell types. Remarkably, there is another dimension to estrogen action by which apoptosis is induced in breast cancer cells. While these mechanisms are not yet completely understood, finding the molecules involved has paved the way for the development of a new drug group. Using ChIP-chip, we have demonstrated that Klf10, a Krüppel-like zinc finger transcription factor, which was induced in response to estrogen, directly modulates the transcription of BI-1 (Bax inhibitor-1; also called the testis-enhanced gene transcript, TEGT). Eventually, the estrogen induced Klf10 and then suppresses BI-1 transcription. The estrogen/Klf10/BI-1 interrelationship was further confirmed using BI-1 promoter and EMSA assays. The estrogen-elicited reduction of BI-1 promoter activity was significantly reversed when the Klf10 binding element was mutated to abolish Klf10 binding. A si-Klf10 antisense-oligo nucleotide was also able to restore BI-1 promoter activity to its pre-estrogen-treatment level. BI-1 is known to regulate stress via the endoplasmic reticulum; in this context down-regulation of BI-1 is able to cause Ca(2+) release and trigger an apoptosis pathway in breast cancer. In our study, Klf10 not only suppressed cellular BI-1 expression but also increased the cytosolic Ca(2+) concentration, eventually causing apoptotic cell death. Based on these results, we suggest the pathway by which estrogen induces apoptosis is possibly through an up-regulation of Klf10 that decreases BI-1 and finally increases the concentration of cytoplasmic calcium.
Department of Life Science, National Cheng Kung University (NCKU), Taiwan.
Ching-Fang
CF
Hsu
Chia-Ling
CL
Sui
Wen-Chi
WC
Wu
Jun-Jie
JJ
Wang
Diane H A
DH
Yang
Yu-Chi
YC
Chen
Winston C Y
WC
Yu
Hung-Shu
HS
Chang
D000230:Adenocarcinoma / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D051765:Early Growth Response Transcription Factors / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D051765:Early Growth Response Transcription Factors; D004967:Estrogens; C098111:KLF10 protein, human; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; C484209:TMBIM6 protein, human; D004958:Estradiol; D002118:Calcium