Abstract
Krüppel-like factor 4 (KLF4) is a transcription factor and functions as a tumor suppressor or tumor promoter in different cancer types. KLF4 regulates many gene expression, thus affects the process of cell proliferation, differentiation, and apoptosis. Recently, KLF4 was reported to induce senescence during the generation of induced pluripotent stem (iPS) cells, but the exact mechanism is still unclear. In this study, we constructed two doxycycline-inducing KLF4 cell models, and demonstrated overexpression of KLF4 could promote cell senescence, detected by senescence-associated β-galactosidase activity assay. Then we confirmed that p21, a key effector of senescence, was directly induced by KLF4. KLF4 could also inhibit survivin, which could indirectly induce p21. By miRNA microarray, we found a series of miRNAs regulated by KLF4 and involved in senescence. We demonstrated that KLF4 could upregulate miR-203, and miR-203 contributed to senescence through miR-203-survivin-p21 pathway. Our results suggest that KLF4 could promote cell senescence through a complex network: miR-203, survivin, and p21, which were all regulated by overexpression of KLF4 and contributed to cell senescence.
Highlights
Krüppel-like factor 4 (KLF4/GKLF/EZF) is a zinc finger transcription factor that belongs to KLF transcription factor family
We demonstrated that KLF4 could upregulate miR-203, and miR-203 contributed to senescence through miR-203-survivin-p21 pathway
Our results suggest that KLF4 could promote cell senescence through a complex network: miR-203, survivin, and p21, which were all regulated by overexpression of KLF4 and contributed to cell senescence
Summary
Krüppel-like factor 4 (KLF4/GKLF/EZF) is a zinc finger transcription factor that belongs to KLF transcription factor family. KLF4 functions as a contextdependent oncogene and tumor suppressor gene [1, 2]. KLF4 can activate or repress gene expression through directly binding on promoter regions. KLF4 could activate expression of p21 ( known as CIP1 and WAF1) [13], while repress the expression of Cyclin E [14]. KLF4 is involved in regulation of cell proliferation, differentiation and apoptosis [15,16,17]. Overexpression of KLF4 inhibits cell proliferation in cell lines and suppresses carcinogenesis and tumor metastasis in mice model [6]. Deletion of KLF4 in mice model promotes carcinogenesis in many types of cancers [18, 19]
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