KLF6

Gene Summary

Gene:KLF6; Kruppel like factor 6
Aliases: GBF, ZF9, BCD1, CBA1, CPBP, PAC1, ST12, COPEB
Location:10p15.2
Summary:This gene encodes a member of the Kruppel-like family of transcription factors. The zinc finger protein is a transcriptional activator, and functions as a tumor suppressor. Multiple transcript variants encoding different isoforms have been found for this gene, some of which are implicated in carcinogenesis. [provided by RefSeq, May 2009]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:Krueppel-like factor 6
Source:NCBIAccessed: 14 March, 2017

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 14 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 14 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: KLF6 (cancer-related)

Chaurasiya S, Hew P, Crosley P, et al.
Breast cancer gene therapy using an adenovirus encoding human IL-2 under control of mammaglobin promoter/enhancer sequences.
Cancer Gene Ther. 2016; 23(6):178-87 [PubMed] Related Publications
Interleukin-2 (IL-2) has been used clinically for the treatment of some malignancies, but the toxicities associated with systemic IL-2 therapy are a major challenge. Here we have determined whether transcriptional targeting of IL-2 to breast cancer (BrCa) using an engineered human mammaglobin promoter/enhancer (MPE2) is a feasible option for reducing IL-2-associated toxicities while still achieving a meaningful antitumor effect. We have constructed nonreplicating adenovirus vectors encoding either a reporter gene (luciferase) or human IL-2 (hIL-2) complementary DNA under control of the MPE2 sequence, the murine cytomegalovirus immediate early (MCMV) promoter or the human telomerase reverse transcriptase (hTERT) promoter. Luciferase and hIL-2 complementary DNAs under the control of the MPE2 sequence in adenovirus vectors were expressed at high levels in BrCa cells and at lower levels in normal cells of human and murine origin. Cancer specificity of the hTERT promoter was found to be similar to that of the MPE2 promoter in cells of human origin, but reduced specificity in murine cells. The MPE2 regulatory sequence demonstrated excellent tissue specificity in a mouse tumor model. Whereas the MCMV promoter-controlled IL-2 vector generated high liver toxicity in mice, the MPE2-controlled IL-2 vector generated little or no liver toxicity. Both IL-2 vectors exerted significant tumor growth delay; however, attempts to further enhance antitumor activity of the IL-2 vectors by combining with the proapoptotic drug procaspase activating compound 1 (PAC1) were unsuccessful.

Yan L, Zhan C, Wu J, Wang S
Expression profile analysis of head and neck squamous cell carcinomas using data from The Cancer Genome Atlas.
Mol Med Rep. 2016; 13(5):4259-65 [PubMed] Free Access to Full Article Related Publications
Head and neck squamous cell carcinoma (HNSCC) is the major histological type of head and neck cancer and no curative treatments are currently available. Using advanced sequencing technologies, The Cancer Genome Atlas (TCGA) has produced large‑scale sequencing data, which provide unprecedented opportunities to reveal molecular mechanisms of cancer. The present study analyzed the mRNA and micro (mi)RNA expression data of HNSCC and normal control tissues released by the TCGA database using a bioinformatics approach to explore underlying molecular mechanisms. The mRNA and miRNA expression data were downloaded from the TCGA database and differentially expressed genes (DEGs) and miRNAs (DEMs) between HNSCC and normal head and neck tissues were identified using TwoClassDif. Subsequently, the gene functions and pathways which are significantly altered in HNSCC were identified using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Regulatory networks among DEGs and DEMs were then constructed, and transcription factors (TFs) potentially regulating the DEGs and DEMs were determined and a TF ‑ miRNA ‑ gene network was established. A total of 2,594 significant DEGs (1,087 upregulated and 1,507 downregulated), and 25 DEMs (8 upregulated and 17 downregulated) were identified in HNSCC compared with normal control samples. These DEGs were significantly enriched in GOs and KEGG pathways such as mitosis, cell cycle, Wnt, JAK/STAT and TLR signaling pathway. CPBP, NF‑AT1 and miR‑1 were situated in the central hub of the TF ‑ miRNA ‑ gene network, underlining their central roles in regulatory processes specific for HNSCC. The present study enhanced the current understanding of the molecular mechanisms underlying HNSCC and may offer novel strategies for its prevention, diagnosis and treatment.

Zhou YL, Xu YJ, Qiao CW
MiR-34c-3p suppresses the proliferation and invasion of non-small cell lung cancer (NSCLC) by inhibiting PAC1/MAPK pathway.
Int J Clin Exp Pathol. 2015; 8(6):6312-22 [PubMed] Free Access to Full Article Related Publications
MicroRNAs have become recognized as key players in the development of malignancy. They are a family of small non-coding RNAs (22 nt~30 nt) that can negatively regulate the expression of cancer-related genes by sequence selective targeting of mRNAs, leading to either mRNA translational repression or degradation. Lung cancer is the leading cause of cancer-related death worldwide with a substantially low survival rate. In this study, we analyzed the expression profile of miR-34c-3p in non-small cell lung cancer (NSCLC) tissues and cell lines, as its participation in some other types of cancer has been shown by previous reports. We found that miR-34c-3p was downregulated both in NSCLC tissues and cell lines. Overexpression of miR-34c-3p suppressed cell proliferation and colony formation and also limited migration and invasion in A549 cells. Furthermore, our results also shown miR-34c-3p reduction was associated with increased PAC1 expression levels in which miR-34c-3p downregulated PAC1 expression by recognizing and binding to specific binding sites in PAC1 3'-UTR. Taken together, our study implicates important roles of miR-34c-3p in NSCLC pathogenesis and implicates its potential application in cancer therapy.

Keung EZ, Akdemir KC, Al Sannaa GA, et al.
Increased H3K9me3 drives dedifferentiated phenotype via KLF6 repression in liposarcoma.
J Clin Invest. 2015; 125(8):2965-78 [PubMed] Free Access to Full Article Related Publications
Liposarcoma (LPS) can be divided into 4 different subtypes, of which well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) are the most common. WDLPS is typically low grade, whereas DDLPS is high grade, aggressive, and carries a worse prognosis. WDLPS and DDLPS frequently co-occur in patients. However, it is not clear whether DDLPS arises independently from WDLPS, or whether epigenomic alterations underly the histopathological differences of these subtypes. Here, we profiled 9 epigenetic marks in tumor samples from 151 patients with LPS and showed elevated trimethylation of histone H3 at Lys9 (H3K9me3) levels in DDLPS tumors. Integrated ChIP-seq and gene expression analyses of patient-derived cell lines revealed that H3K9me3 mediates differential regulation of genes involved in cellular differentiation and migration. Among these, Kruppel-like factor 6 (KLF6) was reduced in DDLPS, with increased H3K9me3 at associated regulatory regions. Pharmacologic inhibition of H3K9me3 with chaetocin decreased DDLPS proliferation and increased expression of the adipogenesis-associated factors PPARγ, CEBPα, and CEBPβ, suggesting that increased H3K9me3 may mediate DDLPS-associated aggressiveness and dedifferentiation properties. KLF6 overexpression partially phenocopied chaetocin treatment in DDLPS cells and induced phenotypic changes that were consistent with adipocytic differentiation, suggesting that the effects of increased H3K9me3 may be mediated through KLF6. In conclusion, we provide evidence of an epigenetic basis for the transition between WDLPS and DDLPS.

Tsvetkova A, Todorova A, Todorov T, et al.
Molecular and clinico-histological data in aggressive prostate cancer patients from Bulgaria.
J BUON. 2015 Mar-Apr; 20(2):498-504 [PubMed] Related Publications
PURPOSE: Metastatic prostate cancer (PCa) is one of the leading causes of death in men worldwide. We report Bulgarian patients with strongly aggressive, castration-resistant PCa.
METHODS: PCA3 overexpression, GSTP1 promoter hyper-methylation, TMPRSS2-ERG gene fusions, IVS1-27G>A in the KLF6 gene and mutations in androgen receptor (AR) gene, for diagnostic purposes were assessed. PCR, real-time PCR (RT-PCR), sequencing, and bisulfite conversion of DNA were applied. We correlated the molecular data to the histological and clinical findings.
RESULTS: The obtained molecular profile in 11 PCa Bulgarian patients coincided with the clinico-histological data of strongly aggressive PCa. Association was detected between the tumor stage (assessed by TNM as T3 and T4) and the detected molecular profile of aggressive cancer behavior with one exception, assessed as T2. None of our patients had positive family history of prostate cancer and no somatic mutations were detected in the AR gene. All patients showed normal genotype with respect to the KLF6 IVS1- 27G>A polymorphism. The rest of the markers were positive in fresh prostatic tissues and biopsies from all patients, whereas only one blood sample showed triple positive result.
CONCLUSIONS: The appearance of PCa-specific markers in blood was considered as a predictor for a PCa (micro) dissemination into the circulation. The GSTP1 promoter hypermethylation is the earliest epigenetic alteration, which indicates cancerous changes and the first and long-lasting marker that is detectable in blood circulation. The molecular profile needs to be strictly monitored during treatment, which is of great help in determining the patient's individual response to therapy.

Tsvetkova A, Todorova A, Todorov T, et al.
Molecular and Clinicopathological Aspects of Prostate Cancer in Bulgarian Probands.
Pathol Oncol Res. 2015; 21(4):969-76 [PubMed] Related Publications
To correlate the molecular data to the clinicopathological parameters in Bulgarian prostate cancer patients. PCA3 overexpression, TMPRSS2-ERG gene fusion, GSTP1 promoter hypermethylation, somatic mutations in the AR gene and the IVS1-27G > A polymorphism in the KLF6 gene were studied. A total of 148 patients were analyzed: 16 aggressive PCa, 83 non-aggressive PCa, 25 BPH and 24 chronic inflammatory diseases. Real-time RT-PCR, DNA sequencing, and bisulfite conversion of DNA, were applied. All cases with aggressive PCa before treatment were tested positive for PCA3 overexpression, expression of a T2-ERG gene fusion product and GSTP1 promoter hypermethylation. No somatic mutations were detected in the AR gene and all patients showed normal KLF6-IVS1-27G > A genotype. The TMPRSS2-ERG positive status correlates with moderate to poorly differentiated prostate tumors and it is considered as unfavorable disease predictor. Positive GSTP1 promoter hypermethylation seems to be highly specific and the earliest epigenetic change in the prostate gland, which indicates the beginning of the pathological process. The appearance of positive molecular markers in blood was considered as a predictor of PCa dissemination. GSTP1 promoter hypermethylation was found as the earliest and a long-lasting epigenetic marker in blood samples of PCa patients, which makes it suitable as a marker for treatment follow-up. The molecular profile of prostate cancer needs to be strictly monitored during the course of disease treatment, which is of a great help in determining the patient's individual therapy response.

Lu XJ, Shi Y, Chen JL, Ma S
Krüppel-like factors in hepatocellular carcinoma.
Tumour Biol. 2015; 36(2):533-41 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a disease with a high incidence and mortality rate worldwide. However, the mechanisms underlying its pathogenesis are still elusive. In recent years, studies on functions of Krüppel-like factors (KLFs) in HCC have shed new light on this field. To date, five members (KLF4, KLF6, KLF8, KLF9, and KLF17) in the KLF family have been reported to function in the pathogenesis of HCC in multiple ways, which hold the potential of deepening and widening our understanding in the initiation and progression of HCC. In this review, we focus on the functions, roles, and regulatory networks of these five KLFs in HCC, summarize key pathways, and propose areas for further investigation, with the hope that this review will provide a reliable and concise reference for readers interested in this area.

Yao YL, Ma J, Wang P, et al.
miR-101 acts as a tumor suppressor by targeting Kruppel-like factor 6 in glioblastoma stem cells.
CNS Neurosci Ther. 2015; 21(1):40-51 [PubMed] Related Publications
BACKGROUND AND AIMS: Great interest persists in useful therapeutic targets in glioblastoma (GBM). Deregulation of microRNAs (miRNAs) expression has been associated with cancer formation through alterations in gene targets. In this study, we reported the role of miR-101 in human glioblastoma stem cells (GSCs) and the potential mechanisms.
METHODS AND RESULTS: Quantitative real-time PCR showed that miR-101 expression was decreased in GSCs. Overexpression of miR-101 reduced the proliferation, migration, invasion, and promoted apoptosis of GSCs. One direct target of miR-101, the transcription factor Kruppel-like factor 6 (KLF6), was identified using the Dual-Luciferase Reporter Assay System, which mediated the tumor suppressor activity of miR-101. This process was coincided with the reduced expression of Chitinase-3-like protein 1 (CHI3L1) whose promoter could be bound with and be promoted by KLF6 demonstrated by luciferase assays and chromatin immunoprecipitation assays. The downregulation of CHI3L1 led to the inactivation of MEK1/2 and PI3K signal pathways. Furthermore, nude mice carrying the tumors of overexpressed miR-101 combined with knockdown of KLF6 produced the smallest tumors and showed the highest survival rate.
CONCLUSIONS: Our findings provided a comprehensive analysis of miR-101 and further defining it as a potential therapeutic candidate for GBM.

Tejero R, Navarro A, Campayo M, et al.
miR-141 and miR-200c as markers of overall survival in early stage non-small cell lung cancer adenocarcinoma.
PLoS One. 2014; 9(7):e101899 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Several treatments in non-small cell lung cancer (NSCLC) are histology-dependent, and the need for histology-related markers is increasing. MicroRNAs (miRNAs) are promising molecular markers in multiple cancers and show differences in expression depending on histological subtype. The miRNA family miR-200 has been associated with the regulation of epithelial-mesenchymal (EMT)/mesenchymal-epithelial transition (MET). EMT involves profound phenotypic changes that include the loss of cell-cell adhesion, the loss of cell polarity, and the acquisition of migratory and invasive properties that facilitates metastasis. A dual role for the miR-200 family in the prognosis of several tumors has been related to tumor cell origin. However, the prognostic role and function of miR-200 family in early-stage NSCLC adenocarcinoma and squamous cell carcinoma (SCC) have not been well established.
METHODS: miRNA expression was determined using TaqMan assays in 155 tumors from resected NSCLC patients. Functional studies were conducted in three NSCLC cell lines: H23, A-549 and HCC-44.
RESULTS: High miR-200c expression was associated with shorter overall survival (OS) in the entire cohort (p = 0.024). High miR-200c (p = 0.0004) and miR-141 (p = 0.009) expression correlated with shorter OS in adenocarcinoma - but not in SCC. In the multivariate analysis, a risk score based on miR-141 and miR-200c expression emerged as an independent prognostic factor for OS in the entire cohort (OR, 2.787; p = 0.033) and in adenocarcinoma patients (OR, 10.649; p = 0.002). Functional analyses showed that miR-200c, was related to mesenchymal-epithelial transition (MET) and affected cell migration and E-cadherin levels, while overexpression of miR-141 reduced KLF6 protein levels and produced an increase of secretion of VEGFA in vitro (H23, p = 0.04; A-549, p = 0.03; HCC-44, p = 0.02) and was associated with higher blood microvessel density in patient tumor samples (p<0.001).
CONCLUSION: High miR-141 and miR-200c expression are associated with shorter OS in NSCLC patients with adenocarcinoma through MET and angiogenesis.

Liang WC, Wang Y, Xiao LJ, et al.
Identification of miRNAs that specifically target tumor suppressive KLF6-FL rather than oncogenic KLF6-SV1 isoform.
RNA Biol. 2014; 11(7):845-54 [PubMed] Free Access to Full Article Related Publications
The Krüppel like factor 6 (KLF6) gene encodes multiple protein isoforms derived from alternative mRNA splicing, most of which are intimately involved in hepatocarcinogenesis and tumor progression. Recent bioinformatics analysis shows that alternative mRNA splicing of the KLF6 gene produces around 16 alternatively spliced variants with divergent or even opposing functions. Intriguingly, the full-length KLF6 (KLF6-FL) is a tumor suppressor gene frequently inactivated in liver cancer, whereas KLF6 splice variant 1 (KLF6-SV1) is an oncogenic isoform with antagonistic function against KLF6-FL. Compelling evidence indicates that miRNA, the small endogenous non-coding RNA (ncRNA), acts as a vital player in modulating a variety of cellular biological processes through targeting different mRNA regions of protein-coding genes. To identify the potential miRNAs specifically targeting KLF6-FL, we utilized bioinformatics analysis in combination with the luciferase reporter assays and screened out two miRNAs, namely miR-210 and miR-1301, specifically targeted the tumor suppressive KLF6-FL rather than the oncogenic KLF6-SV1. Our in vitro experiments demonstrated that stable expression of KLF6-FL inhibited cell proliferation, migration and angiogenesis while overexpression of miR-1301 promoted cell migration and angiogenesis. Further experiments demonstrated that miR-1301 was highly expressed in liver cancer cell lines as well as clinical specimens and we also identified the potential methylation and histone acetylation for miR-1301 gene. To sum up, our findings unveiled a novel molecular mechanism that specific miRNAs promoted tumorigenesis by targeting the tumor suppressive isoform KLF6-FL rather than its oncogenic isoform KLF6-SV1.

Warnke E, Pietsch J, Wehland M, et al.
Spheroid formation of human thyroid cancer cells under simulated microgravity: a possible role of CTGF and CAV1.
Cell Commun Signal. 2014; 12:32 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Multicellular tumor spheroids (MCTS) formed scaffold-free under microgravity are of high interest for research and medicine. Their formation mechanism can be studied in space in real microgravity or on Earth using ground-based facilities (GBF), which simulate microgravity. On Earth, these experiments are more cost-efficient and easily performable. However, each GBF might exert device-specific and altered superimposingly gravity-dependent effects on the cells.
RESULTS: FTC-133 human thyroid cancer cells were cultivated on a 2D clinostat (CN) and a random positioning machine (RPM) and compared with corresponding 1 g control cells. Harvested cell samples were investigated by microscopy, quantitative realtime-PCR and Multi-Analyte Profiling. Spheroid formation and growth occurred during 72 h of cultivation on both devices. Cytokine secretion and gene activation patterns frequently altered in different ways, when the cells were cultured either on the RPM or the CN. A decreased expression of CAV1 and CTGF in MCTS compared to adherent cells was observed after cultivation on both machines.
CONCLUSION: The development of MCTS proceeds similarly on the RPM and the CN resembling the situation observed under real microgravity conditions, while no MCTS formation was observed at 1 g under identical experimental conditions. Simultaneously, changes in the regulation of CTGF and CAV1 appeared in a comparable manner on both machines. A relationship between these molecules and MCTS formation is discussed.

Werner H, Sarfstein R
Transcriptional and epigenetic control of IGF1R gene expression: implications in metabolism and cancer.
Growth Horm IGF Res. 2014; 24(4):112-8 [PubMed] Related Publications
IGF1R plays an important role in protection from apoptosis, regulation of cell growth, differentiation and oncogenic transformation. IGF1R aberrations lead to intrauterine and postnatal growth failure, microcephaly, mental retardation and deafness. High levels of IGF1R are detected in a diversity of human tumors. IGF1R gene transcription is controlled by complex interactions involving DNA-binding and non DNA-binding transcription factors. This review highlights selected examples of a series of tumor suppressors, including the breast cancer gene-1 (BRCA1), p53, the Wilm's tumor protein-1 (WT1) and the von Hippel-Lindau gene (VHL), whose mechanisms of action involve regulation of IGF1R gene expression. IGF1R gene transcription is also dependent on the presence of stimulatory nuclear proteins, including zinc-finger protein Sp1, EWS-WT1, E2F1, Krüppel-like factor-6 (KLF6), high-mobility group A1 (HMGA1), and others. Loss-of-function of tumor suppressor genes, usually caused by mutations, may result in non-functional proteins unable to control IGF1R promoter activity. Impaired regulation of the IGF1R gene is linked to defective cell division, chromosomal instability and increased incidence of cancer.

Hsu TI, Lin SC, Lu PS, et al.
MMP7-mediated cleavage of nucleolin at Asp255 induces MMP9 expression to promote tumor malignancy.
Oncogene. 2015; 34(7):826-37 [PubMed] Related Publications
Nucleolin (NCL) participates in DNA transcription, ribosomal biogenesis and the regulation of RNA stability. However, the contribution of NCL to tumor development is still not clear. Herein, we found that NCL expression correlated with poor prognosis in lung cancer patients. Overexpressed NCL was predominantly cleaved to C-terminal truncated NCL (TNCL). In lung cancer formation, activation of the epidermal growth factor receptor pathway induced NCL expression, and also the expression of matrix metalloproteinase (MMP) 7, which then cleaved NCL at Asp255 to generate TNCL of 55 kDa. TNCL increased the expression of several oncogenes, including MMP9, anaplastic lymphoma kinase (ALK), HIF1a and CBLB, and decreased the expression of tumor suppressors including BRD4, PCM1, TFG and KLF6 by modulating mRNA stability through binding to the 3'-untranslated regions of their transcripts, thus ultimately enhancing metastasis activity. In conclusion, this study identified a novel role of the cleavage form of NCL generated by MMP7 in stabilizing MMP9 mRNA. We also provide a new insight that MMP7 not only cleaves the extracellular matrix to promote tumor invasion but also cleaves NCL, which augment oncogenesis. Blocking NCL cleavage may provide a useful new strategy for lung cancer therapy.

Ozdemir F, Koksal M, Ozmen V, et al.
Mutations and Krüppel-like factor 6 (KLF6) expression levels in breast cancer.
Tumour Biol. 2014; 35(6):5219-25 [PubMed] Related Publications
The transcription factor KLF6 gene has been identified as a tumor suppressor because of its inactivation in several types of cancers by different mechanisms. However, there are no data in the literature investigating the KLF6 mutation rate and expression levels in breast cancer. Therefore, the present study was conducted in order to investigate whether genetic alterations of KLF6 in association with the KLF6 mRNA expression levels may play a role in breast carcinogenesis. For this purpose, we analyzed alterations of the KLF6 gene by direct sequencing and the mRNA levels by reverse transcription-PCR (RT-PCR). In addition to four different non-coding alterations, one missense and two silent alterations were identified in the coding sequence. Reduced KLF6 expression was observed in 41 (83.67 %) of the 49 breast cancer tumors. These findings suggest that the mutation profile of the KLF6 gene in breast tumors is similar to other cancer types. However, these mutations do not exert any effect on the gene expression rate. Downregulation of KLF6 during the progression of breast cancer is independent of the mutations and occurs by a different mechanism.

Lu GY, Huang SM, Liu ST, et al.
Caffeine induces tumor cytotoxicity via the regulation of alternative splicing in subsets of cancer-associated genes.
Int J Biochem Cell Biol. 2014; 47:83-92 [PubMed] Related Publications
Caffeine causes a diverse range of pharmacological effects that are time- and concentration-dependent and reversible. The detailed mechanisms of caffeine in tumor suppression via tumor suppressor protein p53 remain unclear. The isoforms of p53 are physiological proteins that are expressed in normal cells and generated via alternative promoters, splicing sites and/or translational initiation sites. In this study, we investigated how caffeine modulated cell cycle arrest and apoptosis via the expression of various alternatively spliced p53 isoforms. Caffeine reduced p53α expression and induced the expression of p53β, which contains an alternatively spliced p53 C-terminus. In HeLa cells, the expression levels of many serine/arginine-rich splicing factors, including serine/arginine-rich splicing factors 2 and 3, were altered by caffeine. Serine/arginine-rich splicing factor 3 was a promising candidate for the serine/arginine-rich splicing factors responsible for the alternative splicing of p53 in response to caffeine treatment. In addition to p53-dependent functions, multiple target genes of serine/arginine-rich splicing factor 3 suggest that caffeine can regulate epithelial-mesenchymal-transition and hypoxic conditions to inhibit the survival of tumor cells. In summary, our data provide a new pathway of caffeine-modulated tumor suppression via the alternative splicing of the target genes of serine/arginine-rich splicing factor 3.

White JC, Halligan GE, de Chadarévian JP, et al.
Unusual genetic aberrations including a deletion of KLF6 tumor suppressor gene revealed by integrated cytogenetic approaches in a pediatric ewing sarcoma.
J Pediatr Hematol Oncol. 2015; 37(1):e51-4 [PubMed] Related Publications
Ewing sarcoma is the third most common sarcoma in children and young adults. Its characteristic chromosomal rearrangement results in a chimerical EWSR1-ETS transcription factor. Secondary genetic alterations are very common. Membranous expression of CD99 is seen in almost all tumors. We report 2 unusual cytogenetic findings in a pediatric Ewing sarcoma, an insertion of the MIC2 gene encoding CD99 from Xp to 10p and a submicroscopic deletion of the well-known tumor supressor gene KLF6. The latter has not been described previously in pediatric neoplasms. Molecular pathways in tumorigenesis and genetic complexity in cancer are discussed.

DeKelver RC, Lewin B, Lam K, et al.
Cooperation between RUNX1-ETO9a and novel transcriptional partner KLF6 in upregulation of Alox5 in acute myeloid leukemia.
PLoS Genet. 2013; 9(10):e1003765 [PubMed] Free Access to Full Article Related Publications
Fusion protein RUNX1-ETO (AML1-ETO, RUNX1-RUNX1T1) is expressed as the result of the 8q22;21q22 translocation [t(8;21)], which is one of the most common chromosomal abnormalities found in acute myeloid leukemia. RUNX1-ETO is thought to promote leukemia development through the aberrant regulation of RUNX1 (AML1) target genes. Repression of these genes occurs via the recruitment of the corepressors N-COR and SMRT due to their interaction with ETO. Mechanisms of RUNX1-ETO target gene upregulation remain less well understood. Here we show that RUNX1-ETO9a, the leukemogenic alternatively spliced transcript expressed from t(8;21), upregulates target gene Alox5, which is a gene critically required for the promotion of chronic myeloid leukemia development by BCR-ABL. Loss of Alox5 expression reduces activity of RUNX1-ETO9a, MLL-AF9 and PML-RARα in vitro. However, Alox5 is not essential for the induction of leukemia by RUNX1-ETO9a in vivo. Finally, we demonstrate that the upregulation of Alox5 by RUNX1-ETO9a occurs via the C₂H₂ zinc finger transcription factor KLF6, a protein required for early hematopoiesis and yolk sac development. Furthermore, KLF6 is specifically upregulated by RUNX1-ETO in human leukemia cells. This identifies KLF6 as a novel mediator of t(8;21) target gene regulation, providing a new mechanism for RUNX1-ETO transcriptional control.

Hatami R, Sieuwerts AM, Izadmehr S, et al.
KLF6-SV1 drives breast cancer metastasis and is associated with poor survival.
Sci Transl Med. 2013; 5(169):169ra12 [PubMed] Free Access to Full Article Related Publications
Metastasis is the major cause of cancer mortality. A more thorough understanding of the mechanisms driving this complex multistep process will aid in the identification and characterization of therapeutically targetable genetic drivers of disease progression. We demonstrate that KLF6-SV1, an oncogenic splice variant of the KLF6 tumor suppressor gene, is associated with increased metastatic potential and poor survival in a cohort of 671 lymph node-negative breast cancer patients. KLF6-SV1 overexpression in mammary epithelial cell lines resulted in an epithelial-to-mesenchymal-like transition and drove aggressive multiorgan metastatic disease in multiple in vivo models. Additionally, KLF6-SV1 loss-of-function studies demonstrated reversion to an epithelial and less invasive phenotype. Combined, these findings implicate KLF6-SV1 as a key driver of breast cancer metastasis that distinguishes between indolent and lethal early-stage disease and provides a potential therapeutic target for invasive breast cancer.

Jianwei Z, Enzhong B, Fan L, et al.
Effects of Kruppel-like factor 6 on osteosarcoma cell biological behavior.
Tumour Biol. 2013; 34(2):1097-105 [PubMed] Related Publications
Kruppel-like factor 6 (KLF6) is a tumor suppressor gene frequently downregulated in a number of human cancers, including osteosarcoma. However, the role of KLF6 in osteosarcoma remains unclear. This study was aimed at investigating the effects of KLF6 on osteosarcoma cell biological behavior. First, the expression of KLF6 in osteosarcoma cell lines (MG63, SaOS-2, U2OS, and HOS) and a human osteoblastic cell line (hFOB1.19) was detected by Western blotting. Results showed that KLF6 displayed a significant downregulation in osteosarcoma cell lines (MG63, SaOS-2, U2OS, and HOS) compared with human osteoblastic cell line (hFOB1.19). To investigate the role of KLF6 in osteosarcoma cell proliferation, apoptosis, and invasion, we generated human osteosarcoma MG63 cells in which KLF6 was either overexpressed or depleted. The MG63 cell viability, cycle, apoptosis, and invasive ability were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide staining, propidium iodide (PI) staining, Annexin-V-FITC/PI double staining, and Transwell invasion experiment, respectively. Results showed that the viability, proliferation, and invasive abilities were suppressed, and the apoptosis was enhanced in MG63 cells with overexpression of KLF6. The viability, proliferation, and invasive abilities were improved, and the apoptosis was inhibited in MG63 cells with knockdown of KLF6. At the same time, these molecules, including p21, bcl-2, and MMP-9, associated with the events about cell cycle, apoptosis, and invasion, were detected. Results showed that the expressions of bcl-2 and MMP-9 were downregulated, and the expressions of p21 were upregulated in the MG-63 cells with overexpression of KLF6. Taken together, our results suggested that KLF6 could inhibit proliferation and invasion, and facilitate apoptosis of osteosarcoma cells, which might be a potential target for the treatment of osteosarcoma.

Li CR, Su JJ, Wang WY, et al.
Molecular profiling of prostatic acinar morphogenesis identifies PDCD4 and KLF6 as tissue architecture-specific prognostic markers in prostate cancer.
Am J Pathol. 2013; 182(2):363-74 [PubMed] Free Access to Full Article Related Publications
Histopathological classification of human prostate cancer (PCA) relies on the morphological assessment of tissue specimens but has limited prognostic value. To address this deficiency, we performed comparative transcriptome analysis of human prostatic acini generated in a three-dimensional basement membrane that recapitulates the differentiated morphological characteristics and gene expression profile of a human prostate glandular epithelial tissue. We then applied an acinar morphogenesis-specific gene profile to two independent cohorts of patients with PCA (total n = 79) and found that those with tumors expressing this profile, which we designated acini-like tumors, had a significantly lower risk of postoperative relapse compared with those tumors with a lower correlation (hazard ratio, 0.078; log-rank test P = 0.009). Multivariate analyses showed superior prognostic prediction performance using this classification system compared with clinical criteria and Gleason scores. We prioritized the genes in this profile and identified programmed cell death protein 4 (PDCD4) and Kruppel-like factor 6 (KLF6) as critical regulators and surrogate markers of prostatic tissue architectures, which form a gene signature that robustly predicts clinical prognosis with a remarkable accuracy in several large series of PCA tumors (total n = 161; concordance index, 0.913 to 0.951). Thus, by exploiting the genomic program associated with prostate glandular differentiation, we identified acini-like PCA and related molecular markers that significantly enhance prognostic prediction of human PCA.

Stelniec-Klotz I, Legewie S, Tchernitsa O, et al.
Reverse engineering a hierarchical regulatory network downstream of oncogenic KRAS.
Mol Syst Biol. 2012; 8:601 [PubMed] Free Access to Full Article Related Publications
RAS mutations are highly relevant for progression and therapy response of human tumours, but the genetic network that ultimately executes the oncogenic effects is poorly understood. Here, we used a reverse-engineering approach in an ovarian cancer model to reconstruct KRAS oncogene-dependent cytoplasmic and transcriptional networks from perturbation experiments based on gene silencing and pathway inhibitor treatments. We measured mRNA and protein levels in manipulated cells by microarray, RT-PCR and western blot analysis, respectively. The reconstructed model revealed complex interactions among the transcriptional and cytoplasmic components, some of which were confirmed by double pertubation experiments. Interestingly, the transcription factors decomposed into two hierarchically arranged groups. To validate the model predictions, we analysed growth parameters and transcriptional deregulation in the KRAS-transformed epithelial cells. As predicted by the model, we found two functional groups among the selected transcription factors. The experiments thus confirmed the predicted hierarchical transcription factor regulation and showed that the hierarchy manifests itself in downstream gene expression patterns and phenotype.

Muñoz Ú, Puche JE, Hannivoort R, et al.
Hepatocyte growth factor enhances alternative splicing of the Kruppel-like factor 6 (KLF6) tumor suppressor to promote growth through SRSF1.
Mol Cancer Res. 2012; 10(9):1216-27 [PubMed] Related Publications
Alternative splicing of the Krüppel-like factor 6 (KLF6) tumor suppressor into an antagonistic splice variant 1 (SV1) is a pathogenic event in several cancers including hepatocellular carcinoma (HCC) because elevated SV1 is associated with increased tumor metastasis and mortality. Ras activation is one factor that can enhance KLF6 splicing in cancer cells, however pathways driving KLF6 splicing are unknown. Splice site selection is regulated by splice factors that include serine/arginine-rich (SR) proteins such as SRSF1 (ASF-SF2), which in turn is controlled by phosphoinositide 3-kinase (PI3K)/Akt and the mitogen-activated protein kinase (MAPK) signaling pathway. Because signaling pathways downstream of the liver mitogen hepatocyte growth factor (HGF) include Akt, we explored whether HGF induces KLF6 alternative splicing. In HepG2 cells, HGF (25 ng/mL) significantly increases the ratio of SV1/KLF6 full by 40% through phosphorylation of Akt and subsequent downregulation of two splicing regulators, SRSF3 (SRp20) and SRSF1. Decreased SRSF3 levels regulate SRSF1 levels by alternative splicing associated with the nonsense-mediated mRNA decay pathway (AS-NMD), which stimulates cell growth by decreasing p21 levels. Enhanced cell replication through increased KLF6 alternative splicing is a novel growth-promoting pathway of HGF that could contribute to the molecule's mitogenic activity in physiologic liver growth and hepatocellular carcinoma.

Chen K, Chen Y, Zhu XD, et al.
Expression and significance of Kruppel-like factor 6 gene in osteosarcoma.
Int Orthop. 2012; 36(10):2107-11 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Osteosarcoma is primary malignant tumour of bone. Kruppel-like factor 6 (KLF6) is a tumor suppressor gene frequently inactivated in a number of human cancers and a ubiquitously expressed zinc-finger transcription factor. The present study aimed to first explore the relationship between the expression level of the KLF6 gene in osteosarcoma and the occurrence of bone tumours.
METHODS: KLF6 mRNA and protein expression levels in osteosarcoma and normal bone tissue were assayed by real-time quantitative PCR and immunohistochemistry. KLF6 mRNA and protein expression levels in osteosarcoma cells and normal osteoblasts were detected by semi-quantitative reverse transcription PCR and Western blotting, respectively.
RESULTS: Both the expression of KLF6 mRNA and protein in osteosarcoma cells and tissues were significantly lower than that in normal cells and tumour-adjacent tissues.
CONCLUSIONS: KLF6 is a putative tumor suppressor gene involved in osteosarcoma which can be used as a new therapeutic target and an important marker for early diagnosis and postoperative monitoring.

Tsai WC, Hsu SD, Hsu CS, et al.
MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis.
J Clin Invest. 2012; 122(8):2884-97 [PubMed] Free Access to Full Article Related Publications
MicroRNA-122 (miR-122), which accounts for 70% of the liver's total miRNAs, plays a pivotal role in the liver. However, its intrinsic physiological roles remain largely undetermined. We demonstrated that mice lacking the gene encoding miR-122a (Mir122a) are viable but develop temporally controlled steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). These mice exhibited a striking disparity in HCC incidence based on sex, with a male-to-female ratio of 3.9:1, which recapitulates the disease incidence in humans. Impaired expression of microsomal triglyceride transfer protein (MTTP) contributed to steatosis, which was reversed by in vivo restoration of Mttp expression. We found that hepatic fibrosis onset can be partially attributed to the action of a miR-122a target, the Klf6 transcript. In addition, Mir122a(-/-) livers exhibited disruptions in a range of pathways, many of which closely resemble the disruptions found in human HCC. Importantly, the reexpression of miR-122a reduced disease manifestation and tumor incidence in Mir122a(-/-) mice. This study demonstrates that mice with a targeted deletion of the Mir122a gene possess several key phenotypes of human liver diseases, which provides a rationale for the development of a unique therapy for the treatment of chronic liver disease and HCC.

Liu X, Gomez-Pinillos A, Loder C, et al.
KLF6 loss of function in human prostate cancer progression is implicated in resistance to androgen deprivation.
Am J Pathol. 2012; 181(3):1007-16 [PubMed] Free Access to Full Article Related Publications
Inactivation of the transcription factor/tumor suppressor Krüppel-like factor 6 (KLF6) has been described in prostate cancer (PC). This study investigated the prevalence and significance of KLF6 exon 2 mutations and splice variants (SVs) in different stages of human PC progression. By using laser-capture microdissection and recombinant clone isolation of DNA sequences to enhance sensitivity, base changes were found in 20 (24.7%) of 81 PC tissues versus 1 (4%) of 25 normal prostate tissues (P = 0.02). Of 26 base changes, 54% produced nonsynonymous mutations. Only three mutations had driver characteristics (PCs, 4%; NPs, 0%). By using microdissection of fresh-frozen tissues and recombinant isolation of RNA sequences, SVs were found in 39 (75%) of 52 PCs and in 10 (45%) of 22 NPs (P = 0.01). Sixteen different SVs, including 13 unique SVs, were identified that used cryptic splicing sites and encoded nonfunctional KLF6 proteins. PCs that had survived hormone (androgen)-deprivation therapy (n = 21) had a significantly higher (P < 0.05) incidence, number, and expression level of nonfunctional SVs than either NPs (n = 22) or hormone-naïve PCs (n = 25). Forced expression of nonfunctional SVs conferred a survival advantage of androgen-dependent LNCaP cells under castration-simulated culture conditions. Together, these data suggest that decreased availability of functional KLF6 contributes to clinical PC progression. This decrease arises infrequently by somatic mutation and more commonly by the acquisition of SVs that provide a survival advantage under castrate conditions, enabling resistance to hormone therapy.

Chiam K, Ryan NK, Ricciardelli C, et al.
Characterization of the prostate cancer susceptibility gene KLF6 in human and mouse prostate cancers.
Prostate. 2013; 73(2):182-93 [PubMed] Related Publications
BACKGROUND: Krüppel-like factor (KLF) 6 is a candidate tumor suppressor gene in prostate cancer, but the mechanisms contributing to its loss of expression are poorly understood. We characterized KLF6 expression and DNA methylation status during prostate tumorigenesis in humans and mice.
METHODS: KLF6 expression was assessed in matched human non-malignant (NM) and tumor prostate tissues (n = 22) by quantitative real-time PCR (qPCR) and in three independent human prostate cancer cohorts bioinformatically. QPCR for KLF6 expression and methylation-sensitive PCR (MSP) were performed in human prostate LNCaP cancer cells after 5-aza-2'-deoxycytidine treatment. Klf6 protein levels and DNA promoter methylation were assessed in TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) tumors by immunohistochemistry and MSP, respectively.
RESULTS: KLF6 splice variants expression was increased (P = 0.0015) in human prostate tumors compared to NM tissues. Overall, KLF6 was decreased in metastatic compared to primary prostate cancers and reduced expression in primary tumors was associated with a shorter time to relapse (P = 0.0028). Treatment with the demethylating agent 5-aza-2'-deoxycytidine resulted in up-regulation of KLF6 expression (two-fold; P = 0.002) and a decrease in DNA methylation of the KLF6 promoter in LNCaP cells. Klf6 protein levels significantly decreased with progression in the TRAMP model of prostate cancer (P < 0.05), but there was no difference in Klf6 promoter methylation.
CONCLUSION: KLF6 expression was decreased in both clinical prostate cancer and the TRAMP model with disease progression, but this could not be explained by DNA methylation of the KLF6 promoter.

Kiaii S, Kokhaei P, Mozaffari F, et al.
T cells from indolent CLL patients prevent apoptosis of leukemic B cells in vitro and have altered gene expression profile.
Cancer Immunol Immunother. 2013; 62(1):51-63 [PubMed] Related Publications
T cells may have a role in sustaining the leukemic clone in chronic lymphocytic leukemia (CLL). In this study, we have examined the ability of T cells from CLL patients to support the survival of the leukemic B cells in vitro. Additionally, we compared global gene expression of T cells from indolent CLL patients with healthy individuals and multiple myeloma (MM) patients. Apoptosis of purified leukemic B cells was inhibited in vitro when co-cultured with increasing numbers of autologous T cells (p < 0.01) but not autologous B and T cells of normal donors. The anti-apoptotic effect exceeded that of the anti-apoptotic cytokine IL-4 (p = 0.002) and was greater with CD8+ cells (p = 0.02) than with CD4+ cells (p = 0.05). The effect was depended mainly on cell-cell contact although a significant effect was also observed in transwell experiments (p = 0.05). About 356 genes involved in different cellular pathways were deregulated in T cells of CLL patients compared to healthy individuals and MM patients. The results of gene expression profiling were verified for 6 genes (CCL4, CCL5 (RANTES), XCL1, XCL2, KLF6, and TRAF1) using qRT-PCR and immunoblotting. Our results demonstrate that CLL-derived T cells can prevent apoptosis of leukemic B cells and have altered expression of genes that may facilitate the survival of the leukemic clone.

Grande L, Bretones G, Rosa-Garrido M, et al.
Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin.
J Biol Chem. 2012; 287(32):26495-505 [PubMed] Free Access to Full Article Related Publications
Testicular germ cell tumors (TGCTs) are highly responsive to and curable by cisplatin-based chemotherapy even in advanced stages. We have studied the molecular mechanisms involved in the induction of apoptosis in response to cisplatin, and found that proapoptotic Noxa is transcriptionally up-regulated following cisplatin exposure, even in the absence of p53, in NTERA2 cisplatin-sensitive cells but not in 1411HP-resistant cells. Blockade of Noxa reduced the apoptotic response of embryonal carcinoma (EC) NTERA2 cells to cisplatin. A detailed analysis of the Noxa promoter revealed that p73 and Sp1-like factors, Sp1 and KLF6, played key roles in the transcriptional control of this gene. Overexpression of TAp73 induced Noxa whereas the dominant negative isoform ΔNp73, reduced the levels of Noxa after cisplatin exposure in NTERA2 and 2102EP. Interestingly, down-regulation of Sp1 increased Noxa expression in response to cisplatin. However, blockade of KLF6 decreased cisplatin-induced up-regulation of Noxa in EC cell lines. In addition, tissue microarray analyses of TGCTs revealed that expression of Noxa correlates with good clinical prognosis in patients with embryonal carcinoma. Thus, our data show the transcriptional network that regulates Noxa in EC cells, which is key for their apoptotic response to cisplatin-based chemotherapy, and propose Noxa as a predictive factor of therapeutic response.

Eronen L, Toivonen H
Biomine: predicting links between biological entities using network models of heterogeneous databases.
BMC Bioinformatics. 2012; 13:119 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Biological databases contain large amounts of data concerning the functions and associations of genes and proteins. Integration of data from several such databases into a single repository can aid the discovery of previously unknown connections spanning multiple types of relationships and databases.
RESULTS: Biomine is a system that integrates cross-references from several biological databases into a graph model with multiple types of edges, such as protein interactions, gene-disease associations and gene ontology annotations. Edges are weighted based on their type, reliability, and informativeness. We present Biomine and evaluate its performance in link prediction, where the goal is to predict pairs of nodes that will be connected in the future, based on current data. In particular, we formulate protein interaction prediction and disease gene prioritization tasks as instances of link prediction. The predictions are based on a proximity measure computed on the integrated graph. We consider and experiment with several such measures, and perform a parameter optimization procedure where different edge types are weighted to optimize link prediction accuracy. We also propose a novel method for disease-gene prioritization, defined as finding a subset of candidate genes that cluster together in the graph. We experimentally evaluate Biomine by predicting future annotations in the source databases and prioritizing lists of putative disease genes.
CONCLUSIONS: The experimental results show that Biomine has strong potential for predicting links when a set of selected candidate links is available. The predictions obtained using the entire Biomine dataset are shown to clearly outperform ones obtained using any single source of data alone, when different types of links are suitably weighted. In the gene prioritization task, an established reference set of disease-associated genes is useful, but the results show that under favorable conditions, Biomine can also perform well when no such information is available.The Biomine system is a proof of concept. Its current version contains 1.1 million entities and 8.1 million relations between them, with focus on human genetics. Some of its functionalities are available in a public query interface at http://biomine.cs.helsinki.fi, allowing searching for and visualizing connections between given biological entities.

Sangodkar J, Dhawan NS, Melville H, et al.
Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response.
J Clin Invest. 2012; 122(7):2637-51 [PubMed] Free Access to Full Article Related Publications
EGFR activation is both a key molecular driver of disease progression and the target of a broad class of molecular agents designed to treat advanced cancer. Nevertheless, resistance develops through several mechanisms, including activation of AKT signaling. Though much is known about the specific molecular lesions conferring resistance to anti-EGFR-based therapies, additional molecular characterization of the downstream mediators of EGFR signaling may lead to the development of new classes of targeted molecular therapies to treat resistant disease. We identified a transcriptional network involving the tumor suppressors Krüppel-like factor 6 (KLF6) and forkhead box O1 (FOXO1) that negatively regulates activated EGFR signaling in both cell culture and in vivo models. Furthermore, the use of the FDA-approved drug trifluoperazine hydrochloride (TFP), which has been shown to inhibit FOXO1 nuclear export, restored sensitivity to AKT-driven erlotinib resistance through modulation of the KLF6/FOXO1 signaling cascade in both cell culture and xenograft models of lung adenocarcinoma. Combined, these findings define a novel transcriptional network regulating oncogenic EGFR signaling and identify a class of FDA-approved drugs as capable of restoring chemosensitivity to anti-EGFR-based therapy for the treatment of metastatic lung adenocarcinoma.

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