Krüppel-like transcription factor 4 contributes to maintenance of telomerase activity in stem cells.
The zinc finger Krüppel-like transcription factor 4 (KLF4) has been implicated in cancer formation and stem cell regulation. However, the function of KLF4 in tumorigenesis and stem cell regulation are poorly understood due to limited knowledge of its targets in these cells. In this study, we have revealed a surprising link between KLF4 and regulation of telomerase that offers important insight into how KLF4 contributes to cancer formation and stem cell regulation. KLF4 sufficiently activated expression of the human telomerase catalytic subunit, human telomerase reverse transcriptase (hTERT), in telomerase-low alternative lengthening of telomeres (ALT), and fibroblast cells, while downregulation of KLF4 reduced its expression in cancerous and stem cells, which normally exhibits high expression. Furthermore, KLF4-dependent induction of hTERT was mediated by a KLF4 binding site in the proximal promoter region of hTERT. In human embryonic stem cells, expression of hTERT replaced KLF4 function to maintain their self-renewal. Therefore, our findings demonstrate that hTERT is one of the major targets of KLF4 in cancer and stem cells to maintain long-term proliferation potential.
Wong
Chui-Wei
CW
Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Hou
Pei-Shan
PS
Tseng
Shun-Fu
SF
Chien
Chung-Liang
CL
Wu
Kou-Juey
KJ
Chen
Hsin-Fu
HF
Ho
Hong-Nerng
HN
Kyo
Satoru
S
Teng
Shu-Chun
SC
D000818:Animals; D001665:Binding Sites; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000201:enzymology*; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques
C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C509186:TERT protein, human; D019098:Telomerase