KLF4 is downregulated but not mutated during human esophageal squamous cell carcinogenesis and has tumor stage-specific functions

Abstract

The transcriptional regulator Kr€ uppel-like factor 4 (KLF4) is decreased in human esophageal squamous cell cancer (ESCC), and Klf4 deletion in mice produces squamous cell dysplasia. Nonetheless the mechanisms of KLF4 downregulation in ESCC and the functions of KLF4 during ESCC development and progression are not well understood. Here, we sought to define the regulation of KLF4 and delineate the stage-specific effects of KLF4 in ESCC. We found that KLF4 expression was decreased in human ESCC and in 8 of 9 human ESCC cell lines. However, by genomic sequencing, we observed no KLF4 mutations or copy number changes in any of 52 human ESCC, suggesting other mechanisms for KLF4 silencing. In fact, KLF4 expression in human ESCC cell lines was increased by the DNA methylation inhibitor 5-azacytidine, suggesting an epigenetic mechanism for KLF4 silencing. Surprisingly, while KLF4 decreased in high-grade dysplasia and early stage tumors, KLF4 increased with advanced cancer stage, and KLF4 expression in ESCC was inversely correlated with survival. Interestingly, KLF4 promoted invasion of human ESCC cells, providing a functional link to the stage-specific expression of KLF4. Taken together, these findings suggest that KLF4 loss is necessary for esophageal tumorigenesis but that restored KLF4 expression in ESCC promotes tumor spread. Thus, the use of KLF4 as a diagnostic and therapeutic target in cancer requires careful consideration of context.Abbreviations: KLF4, Kr€ uppel-like factor 4; ESCC, esophageal squamous cell cancer; SNP, single nucleotide polymorphism; HDAC, histone deacetylase

Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma

“…Most samples were available as tissue microarrays (TMAs) 67 , 68 containing primary ESCC ( n = 171), carcinoma in situ (CIS; n = 9), IEN ( n = 7), and normal mucosa ( n = 114). Samples with NOTCH1 mutations ( n = 4; E755*, D469Y, R1279D, and D1457G) and wild-type NOTCH1 ( n = 15) were identified by DNA sequencing (SRP072948) 69 . Given the limitation of TMAs to assess intratumoral cancer cell heterogeneity 70 , we examined whole paraffin blocks ( n = 244) by Hematoxylin and Eosin (H&E) staining and IHC, as described below, following preliminary analysis with TMAs.…”

Overexpression of Krüppel-Like Factor 4 Suppresses Migration and Invasion of Non-Small Cell Lung Cancer Through c-Jun-NH2-Terminal Kinase/Epithelial-Mesenchymal Transition Signaling Pathway

“…Tango H et al demonstrated that KLF4 was downregulated in anaplastic meningioma compared with low-grade meningiomas, and KLF4 could reduce the invasive ability of anaplastic meningioma stem-like cells (Tang et al, 2017). Yang Y et al found that KLF4 increased with advanced cancer stage and promoted invasion of human esophageal squamous cell cancer cells (Yang and Katz, 2016). A meta-analysis of 2,988 patients showed that low KLF4 expression was related to worse overall survival and disease-free survival in solid tumor (Yu et al, 2018).…”

SP and KLF Transcription Factors in Digestive Physiology and Diseases

“…Although KLF4 expression is decreased in early-stage tumors, increased expression is observed in advanced tumors, and restored expression of KLF4 in human ESCC cells is important for tumor metastasis 31 . On the other hand, decreased expression of KLF5 is observed in human ESCC 27, 28, 33 .…”

“…KLF4 expression is decreased in 8 of 9 human ESCC cell lines 31 . Gene expression profiling of ESCCs shows that decreased KLF4 correlates with reduced expression of keratin 13 ( KRT13 )—an indicator of cell differentiation in ESCC.…”