Identification of KLF17 as a novel epithelial to mesenchymal transition inducer via direct activation of TWIST1 in endometrioid endometrial cancer.
Krüppel-like factor 17 (KLF17), a member of the KLF transcription factor family, has been shown to inhibit the epithelial-mesenchymal transition (EMT) and tumor growth. However, the expression, the cellular function and the mechanism of KLF17 in endometrioid endometrial cancer (EEC; a dominant type of endometrial cancer) remain elusive. Here, we report that among the KLF family members, KLF17 was consistently upregulated in EEC cell lines compared with immortalized endometrial epithelial cells. Overexpression of KLF17 in EEC cell lines induced EMT and promoted cell invasion and drug resistance, resulting in increased expression of TWIST1. In contrast, KLF17 suppression reversed EMT, diminished cell invasion, restored drug sensitivity and suppressed TWIST1 expression. Luciferase assays, site-directed mutagenesis and transcription factor DNA-binding analysis demonstrated that KLF17 transactivates TWIST1 expression by directly binding to the TWIST1 promoter. Knockdown of TWIST1 prevented KLF17-induced EMT. Consistent with these results, both KLF17 and TWIST1 levels were found to be elevated in EECs compared with normal tissues. KLF17 expression positively correlated with tumor grade but inversely correlated with estrogen and progesterone receptor expression. Thus, KLF17 may have an oncogenic role during EEC progression via initiating EMT through the regulation of TWIST1.
Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, Sapporo 0608638, Japan.
Peixin
P
Dong
Masanori
M
Kaneuchi
Ying
Y
Xiong
Liping
L
Cao
Muyan
M
Cai
Xishi
X
Liu
Sun-Wei
SW
Guo
Jingfang
J
Ju
Nan
N
Jia
Yosuke
Y
Konno
Hidemichi
H
Watari
Masayoshi
M
Hosaka
Satoko
S
Sudo
Noriaki
N
Sakuragi
D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D016889:Endometrial Neoplasms / Q000473:pathology* / Q000503:physiopathology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D051879:Twist-Related Protein 1 / Q000502:physiology*
D017931:DNA Primers; C510638:KLF17 protein, human; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1