Attenuation of Krüppel-Like Factor 4 Facilitates Carcinogenesis by Inducing G1/S Phase Arrest in Clear Cell Renal Cell Carcinoma

Abstract

Krüppel-like factor 4 (KLF4) is a transcription factor with diverse functions in various cancer types; however, the function of KLF4 in clear cell renal cell carcinoma (ccRCC) carcinogenesis remains unknown. In this study, we initially examined KLF4 expression by using a cohort of surgically removed ccRCC specimens and cell lines. Results indicated that the transcription and translation of KLF4 were lower in ccRCC tissues than in patient-matched normal tissues. Furthermore, the KLF4 expression was significantly downregulated in the five ccRCC cell lines at protein and mRNA levels compared with that in normal renal proximal tubular epithelial cell lines (HKC). KLF4 downregulation was significantly correlated with tumor stage and tumor diameter. Promoter hypermethylation may contribute to its low expression. In addition, in vitro studies indicated that the KLF4 overexpression significantly inhibited proliferation in human ccRCC cell lines 786-O and ACHN. Moreover, the KLF4 overexpression arrested the cell cycle progress at the G1/S phase transition by upregulating p21WAF1/CIP1 expression and downregulating cyclin D1 expression, KLF4 knockdown in HKC cells did the opposite. In vivo studies confirmed the anti-proliferative effect of KLF4. Our results suggested that KLF4 had an important function in suppressing the growth of ccRCC.

Krüppel -Like Factor 8 is a Stress-Responsive Transcription Factor that Regulates Expression of HuR

“…4A). Others had previously demonstrated the presence of KLF 4 and KLF6 in proximal tubule cells [39, 40]. A review of the literature indicated that KLF8 in particular shared many functional attributes with HuR, including promotion of tumor development, growth, and metastasis, and a commonality of target genes [41].…”

“…Few KLF proteins have been characterized in proximal tubules. One example is KLF4, which functions as a tumor suppressor in a number of tissues, and was recently shown to be expressed in proximal tubule cells and downregulated in renal cell carcinoma tissues [40]. Additionally, in a screen for mRNAs that are upregulated in the earliest stages of renal ischemia/reperfusion injury, KLF6 (formerly Zf9) was detected.…”

FOXK2 suppresses the malignant phenotype and induces apoptosis through inhibition of EGFR in clear‐cell renal cell carcinoma

“…21,22 All human tissues and xenograft tumor tissues were fixed in 10% neutral formalin and embedded in paraffin. 21,22 All human tissues and xenograft tumor tissues were fixed in 10% neutral formalin and embedded in paraffin.…”

Potential protective role of Grainyhead‐like genes in the development of clear cell renal cell carcinoma

“…These SNPs may affect mRNA stability or alter the binding of transcription factors to the promoter regions of GRHL genes (Table ). Of these, KLF4 (Krüppel‐like factor 4) is a potential suppressor of ccRCC . There is also evidence pointing to the involvement of STAT4 (signal transducer and activator of transcription 4) and STAT5A/B in ccRCC .…”