Kruppel-like factor 4 is a novel mediator of selenium in growth inhibition.
A previous prevention trial showed that selenium supplementation was effective in reducing (by 50%) the incidence of prostate cancer. Selenium has been reported to inhibit the growth of prostate cancer cells in vitro. Multiple mechanisms are likely to be operative in the underlying effect of selenium. Here, we report that Krüppel-like factor 4 (KLF4), a transcription factor of the KLF family, is an important target of selenium. We found that selenium up-regulates KLF4 expression and increases the DNA-binding activity of KLF4 in both the androgen-dependent LNCaP and the androgen-independent PC-3 human prostate cancer cells. The increase of KLF4 mRNA is accounted for primarily by enhanced transcription, although the contribution of a slight abatement in mRNA degradation cannot be ruled out. KLF4 knockdown using short interference RNA significantly weakens the effects of selenium on DNA synthesis inhibition, apoptosis induction, and the expression of three KLF4 target genes, cyclin D1, p21/WAF1, and p27/Kip1. In addition, the overexpression of KLF4 not only leads to an induction of apoptosis in the control cells, but also enhances the DNA synthesis-suppressive and-proapoptotic activities of selenium. Taken together, our results suggest that KLF4 plays a key role in mediating the growth-inhibitory effect of selenium in prostate cancer cells.
Liu
Shuang
S
Department of Structural & Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Zhang
Haitao
H
Zhu
Liyu
L
Zhao
Lijuan
L
Dong
Yan
Y
D001973:Bromodeoxyuridine / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D016566:Organoselenium Compounds / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012643:Selenium / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D004273:DNA, Neoplasm; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D016566:Organoselenium Compounds; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C008493:methylselenic acid; D001973:Bromodeoxyuridine; D012643:Selenium