Gene Summary

Gene:KLF6; Kruppel like factor 6
Aliases: GBF, ZF9, BCD1, CBA1, CPBP, PAC1, ST12, COPEB
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:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:Krueppel-like factor 6
Source:NCBIAccessed: 31 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 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)

Syafruddin SE, Rodrigues P, Vojtasova E, et al.
A KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma.
Nat Commun. 2019; 10(1):1152 [PubMed] Free Access to Full Article Related Publications
Transcriptional networks are critical for the establishment of tissue-specific cellular states in health and disease, including cancer. Yet, the transcriptional circuits that control carcinogenesis remain poorly understood. Here we report that Kruppel like factor 6 (KLF6), a transcription factor of the zinc finger family, regulates lipid homeostasis in clear cell renal cell carcinoma (ccRCC). We show that KLF6 supports the expression of lipid metabolism genes and promotes the expression of PDGFB, which activates mTOR signalling and the downstream lipid metabolism regulators SREBF1 and SREBF2. KLF6 expression is driven by a robust super enhancer that integrates signals from multiple pathways, including the ccRCC-initiating VHL-HIF2A pathway. These results suggest an underlying mechanism for high mTOR activity in ccRCC cells. More generally, the link between super enhancer-driven transcriptional networks and essential metabolic pathways may provide clues to the mechanisms that maintain the stability of cell identity-defining transcriptional programmes in cancer.

Luo D, Chen J, Huang S, et al.
MicroRNA‑18b acts as an oncogene in gastric cancer by directly targeting Kruppel‑like factor 6.
Mol Med Rep. 2019; 19(3):1926-1934 [PubMed] Related Publications
Gastric cancer (GC) is the fourth most frequently occurring cancer and the second most common cause of cancer‑associated mortality worldwide. An increasing number of studies have reported that microRNAs (miRNAs/miRs) contribute to the regulation of GC development and progression. Therefore, investigation of the miRNAs involved in the development of GC may result in identification of an effective therapeutic target for patients with this malignancy. miR‑18b has been reported to be aberrantly expressed in several types of human cancer. However, the expression pattern, biological role and specific functional mechanism of miR‑18b in GC remains to be elucidated. In the present study, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis revealed that miR‑18b was significantly upregulated in GC tissues and cell lines compared with normal gastric tissues and the human gastric epithelial immortalized cell line GES‑1, respectively. High miR‑18b expression was significantly associated with lymph node metastasis, invasive depth and the Tumor Node Metastasis stage of patients with GC. Additionally, functional assays indicated that the inhibition of miR‑18b attenuated cell proliferation and invasion in GC. Furthermore, Kruppel‑like factor (KLF)‑6 was identified as a direct target gene of miR‑18b in GC, from the results of bioinformatics analysis, a luciferase reporter assay, RT‑qPCR and western blot analysis. An inverse association was observed between miR‑18b and KLF6 mRNA levels in GC tissues. KLF6 knockdown partially abrogated the effects of miR‑18b inhibition on GC cell proliferation and invasion. Therefore, miR‑18b/KLF6 targeted therapy may provide a promising treatment for patients with GC.

Liu JX, Li W, Li JT, et al.
Screening key long non-coding RNAs in early-stage colon adenocarcinoma by RNA-sequencing.
Epigenomics. 2018; 10(9):1215-1228 [PubMed] Related Publications
AIM: We aim to identify the key long noncoding RNAs (lncRNAs) in early-stage colon adenocarcinoma (COAD).
PATIENTS & METHODS: Compared with colonic intraepithelial neoplasia, differentially expressed lncRNAs (DElncRNAs) in early-stage COAD were obtained by RNA-sequencing. Our previous work has obtained the differentially expressed mRNAs and miRNAs (DEmRNAs and DEmiRNAs) in early-stage COAD. DEmiRNA-DElncRNA-DEmRNA interaction analysis and functional annotation were performed. Validation of expression and receiver-operating characteristic analyses were performed based on The Cancer Genome Atlas.
RESULTS: Seventy-nine significantly DElncRNAs in early-stage COAD were obtained. MiR-153-3p-TUG1-DAPK1/ARNT2/KLK3/PLD1/SMAD2 and miR-153-3p-SNHG17-COL11A1/IGFBP3/KLF6 interactions were associated with early-stage COAD. Five DElncRNAs (ELFN1-AS1, LINC01234, SNHG17, UCA1 and LOC101929549) involved in early-stage COAD with potential diagnostic value.
CONCLUSION: LncRNAs involve in early-stage COAD by interaction with COAD-regulated genes and miRNAs.

Qadir F, Aziz MA, Sari CP, et al.
Transcriptome reprogramming by cancer exosomes: identification of novel molecular targets in matrix and immune modulation.
Mol Cancer. 2018; 17(1):97 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Exosomes are extracellular vesicles released by almost all cell types, including cancer cells, into bodily fluids such as saliva, plasma, breast milk, semen, urine, cerebrospinal fluid, amniotic fluid, synovial fluid and sputum. Their key function being intercellular communication with both neighbouring as well as distant cells. Cancer exosomes have been shown to regulate organ-specific metastasis. However, little is known about the functional differences and molecular consequences of normal cells responding to exosomes derived from normal cells compared to those derived from cancer cells.
METHODS: Here, we characterised and compared the transcriptome profiles of primary human normal oral keratinocytes (HNOK) in response to exosomes isolated from either primary HNOK or head and neck squamous cell carcinoma (HNSCC) cell lines.
RESULTS: In recipient HNOK cells, we found that regardless of normal or cancer derived, exosomes altered molecular programmes involved in matrix modulation (MMP9), cytoskeletal remodelling (TUBB6, FEZ1, CCT6A), viral/dsRNA-induced interferon (OAS1, IFI6), anti-inflammatory (TSC22D3), deubiquitin (OTUD1), lipid metabolism and membrane trafficking (BBOX1, LRP11, RAB6A). Interestingly, cancer exosomes, but not normal exosomes, modulated expression of matrix remodelling (EFEMP1, DDK3, SPARC), cell cycle (EEF2K), membrane remodelling (LAMP2, SRPX), differentiation (SPRR2E), apoptosis (CTSC), transcription/translation (KLF6, PUS7). We have also identified CEP55 as a potential cancer exosomal marker.
CONCLUSIONS: In conclusion, both normal and cancer exosomes modulated unique gene expression pathways in normal recipient cells. Cancer cells may exploit exosomes to confer transcriptome reprogramming that leads to cancer-associated pathologies such as angiogenesis, immune evasion/modulation, cell fate alteration and metastasis. Molecular pathways and biomarkers identified in this study may be clinically exploitable for developing novel liquid-biopsy based diagnostics and immunotherapies.

Qin J, Meng F, Chu Z, Gu X
Association between Krüppel like factor 6 intervening sequence 1-27 G > A and cancer susceptibility: A meta-analysis.
J Cancer Res Ther. 2018; 14(Supplement):S499-S504 [PubMed] Related Publications
Background/Objective: It has been reported that Krüppel like factor 6 intervening sequence (KLF6 IVS) 1-27 G > A might be associated with cancer susceptibility. Here, we conducted a meta-analysis to summarize and clarify this association.
Materials and Methods/Main Results: A systematic search of studies on the association between KLF6 IVS 1-27 G > A, and cancer susceptibility was conducted in databases. Odds ratios and 95% confidence intervals were used to pool the effect size. Seven articles were included in our meta-analysis. Overall and in prostate cancer, population-based subgroup overall and Caucasian subgroup overall, no evidence was found for the association between KLF6 IVS 1-27 G > A polymorphism and cancer susceptibility in any genetic model and the results showed stability in sensitivity analyses.
Conclusions: KLF6 IVS 1-27 G > A may not be associated with cancer susceptibility, especially the susceptibility of unselected prostate cancer. However, there was insufficient data to fully confirm the association between KLF6 IVS 1-27 G > A and familial prostate cancer, sporadic prostate cancer, gastric cancer, and cancers from different ethnicity, and the results should be interpreted with caution.

Liu Z, Dai J, Shen H
Systematic analysis reveals long noncoding RNAs regulating neighboring transcription factors in human cancers.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(9 Pt B):2785-2792 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) are proposed to play essential roles in regulating gene transcription. Moreover, a subset has been implicated in modulating the expression of the nearby loci. Here we systematically evaluated the relationship between lncRNAs and their neighboring genes based on transcriptome expression profiles from 4900 samples across 12 cancer types. Our findings reveal that lncRNAs, especially those of high syntenic conservation across species, are spatially correlated with transcription factors across the genome. Combining the methods of conservation, co-expression, and causal inference test, we identified a list of 28 lncRNA/TF regulatory pairs across 12 TCGA cancer types, and 19 of which were further confirmed in additional cancer cell lines. Several of these pairs, including PTV1/MYC and GATA6-AS1/GATA6, show prior evidence of regulatory relationships. Other candidates such as LINC00261/FOXA2 and PITRM1-AS1/KLF6 were novel. Our study highlights the significant roles of lncRNAs in tumorigenesis and provides a comprehensive overview of lncRNA regulation on its neighboring TF genes in human cancers.

Antonopoulou E, Ladomery M
Targeting Splicing in Prostate Cancer.
Int J Mol Sci. 2018; 19(5) [PubMed] Free Access to Full Article Related Publications
Over 95% of human genes are alternatively spliced, expressing splice isoforms that often exhibit antagonistic functions. We describe genes whose alternative splicing has been linked to prostate cancer; namely

Kokhaei P, Hojjat-Farsangi M, Mozaffari F, et al.
Autologous T cells expressing the oncogenic transcription factor KLF6-SV1 prevent apoptosis of chronic lymphocytic leukemia cells.
PLoS One. 2018; 13(2):e0192839 [PubMed] Free Access to Full Article Related Publications
Crosstalk between leukemic cells and the tumor microenvironment is of importance in chronic lymphocytic leukemia (CLL). T cells seem to sustain the survival of CLL cells by various mechanisms. The Krüppel-like family of transcription factors (KLFs) are identified as regulators of proliferation and cell death. In the present study, we analyzed the expression of the wild type (WT) gene KLF6 and the oncogenic splice variant 1 (KLF6-SV1) at the mRNA level in subsets of T cells from CLL patients (n = 29), multiple myeloma patients (n = 6) and normal donors (n = 10). RNA Silencing was used for wtKLF6 and KLF6-SV1. Tumor cell apoptosis was measured. A significant overexpression of wtKLF6 and KLF6-SV1 in T cells of CLL patients compared to normal donors and myeloma patients was noted (p<0.002). Western blot showed that both wtKLF6 and KLF6-SV1 were expressed in purified T cells from CLL patients. KLF6-SV1 siRNA transfection induced a significant down-regulation of KLF6-SV1 in CLL T cells, which lost the capability to sustain the growth of leukemic cells. However, no such a significant effect was seen after wtKLF6 transfection of the autologous T cells. The results suggest that KLF6-SV1 may play a role in the regulation of survival CLL cells.

Islam F, Gopalan V, Vider J, et al.
MiR-142-5p act as an oncogenic microRNA in colorectal cancer: Clinicopathological and functional insights.
Exp Mol Pathol. 2018; 104(1):98-107 [PubMed] Related Publications
OBJECTIVES: miR-142-5p was noted aberrantly expressed and plays important roles in different pathophysiological conditions in human. The present study aims to examine the expression of miR-142-5p and its association with clinicopathological factors in a large cohort of patients with colorectal cancer. In addition, the cellular effects of miR-142-5p and its interacting targets in colon cancer cells were investigated.
METHODS: Expression of miR-142-5p in colorectal cancer tissues (n=125) and colon cancer cell lines were analysed using real-time polymerase chain reaction. In vitro assays (cell proliferation, wound healing and colony formation) were used to study the miR-142-5p induced cellular effects. Western blots were used to examine the modulation of FAM134B, KRAS, EPAS1 and KLF6 proteins expression followed by miR-142-5p expression-manipulation.
RESULTS: Significant high expression of miR-142-5p was noted in cancer tissues and cells when compared to the controls (p<0.001). Overexpression of miR-142-5p in patients with colorectal cancer was common (72%; 90/125). miR-142-5p overexpression was associated with cancer in the proximal colorectum and with B-raf positive patients (p=0.05). Exogenous overexpression of miR-142-5p resulted in significantly increased cell proliferation, colony formation, and wound healing capacities, whereas inhibition of endogenous miR-142-5p led reduced cancer growth properties. The cellular effects of miR-142-5p were mediated by the modulation of tumour suppressor KLF6 expression, as the expression of miR-142-5p and KLF6 protein are inversely correlated in colon cancer cells.
CONCLUSION: High miR-142-5p expression was associated with the biological aggressiveness of cancer. Thus, suppression of miR-142-5p could be a therapeutic strategy for patients with colorectal cancers.

Wehrkamp CJ, Natarajan SK, Mohr AM, et al.
miR-106b-responsive gene landscape identifies regulation of Kruppel-like factor family.
RNA Biol. 2018; 15(3):391-403 [PubMed] Free Access to Full Article Related Publications
MicroRNA dysregulation is a common feature of cancer and due to the promiscuity of microRNA binding this can result in a wide array of genes whose expression is altered. miR-106b is an oncomiR overexpressed in cholangiocarcinoma and its upregulation in this and other cancers often leads to repression of anti-tumorigenic targets. The goal of this study was to identify the miR-106b-regulated gene landscape in cholangiocarcinoma cells using a genome-wide, unbiased mRNA analysis. Through RNA-Seq we found 112 mRNAs significantly repressed by miR-106b. The majority of these genes contain the specific miR-106b seed-binding site. We have validated 11 genes from this set at the mRNA level and demonstrated regulation by miR-106b of 7 proteins. Combined analysis of our miR-106b-regulated mRNA data set plus published reports indicate that miR-106b binding is anchored by G:C pairing in and near the seed. Novel targets Kruppel-like factor 2 (KLF2) and KLF6 were verified both at the mRNA and at the protein level. Further investigation showed regulation of four other KLF family members by miR-106b. We have discovered coordinated repression of multiple members of the KLF family by miR-106b that may play a role in cholangiocarcinoma tumor biology.

Zhang S, Zhang JY, Lu LJ, et al.
MiR-630 promotes epithelial ovarian cancer proliferation and invasion via targeting KLF6.
Eur Rev Med Pharmacol Sci. 2017; 21(20):4542-4547 [PubMed] Related Publications
OBJECTIVE: MicroRNAs play critical roles in post-translational gene expression. The current study was to investigate the effects of miR-630 in epithelial ovarian cancer.
PATIENTS AND METHODS: Thirty epithelial ovarian cancer tissue and thirty normal ovarian tissue samples were collected and were detected miR-630 expression level with qRT-PCR. MiR-630 mimics, inhibitors and negative controls were transfected into SKOV3 and Cell Counting Kit-8 (CCK-8) assay, and transwell experiment were performed to detect the proliferation rate and migration, respectively. The luciferase reporter assay was utilized to identify miR-630's target gene. Balb/c nude mice were utilized to verify the effect of miR-630 in vivo.
RESULTS: QRT-PCR showed a significantly high miR-630 expression in epithelial ovarian cancer relative to normal ovarian tissue. The miR-630 overexpression promoted epithelial ovarian cancer cell SKOV3 proliferation and migration. Krüppel-like factor 6 (KLF6) was predicted as the target of miR-630. In vivo study also verified that miR-630 overexpression stimulated ovarian cancer growth.
CONCLUSIONS: We propose that targeting miR-630 might be a promising therapeutic approach for ovarian cancer.

Yang F, Ma J, Tang Q, et al.
MicroRNA-543 promotes the proliferation and invasion of clear cell renal cell carcinoma cells by targeting Krüppel-like factor 6.
Biomed Pharmacother. 2018; 97:616-623 [PubMed] Related Publications
MicroRNA-543 (miR-543) has been suggested as an important regulator of the development and progression of various cancer types. However, the role and biological function of miR-543 in clear cell renal cell carcinoma (ccRCC) remains unclear. Here, we found that miR-543 expression was significantly increased in tumor tissues from ccRCC patients and ccRCC cell lines. We found that overexpression of miR-543 markedly promoted the proliferation and invasion of ccRCC cells, whereas suppression of miR-543 had the opposite effects. Krüppel-like factor 6 (KLF6) was identified as a target gene of miR-543. Furthermore, we found that miR-543 negatively regulates the expression of KLF6 and p21 in ccRCC cells. Overexpression of KLF6 markedly attenuated the oncogenic effect of miR-543 overexpression. Moreover, knockdown of KLF6 significantly reversed the antitumor effect of miR-543 inhibition. Overall, our results demonstrate that miR-543 promotes the proliferation and invasion of ccRCC cells by targeting KLF6 and suggest that miR-543 may serve as a potential therapeutic target for treatment of ccRCC.

Zhang B, Guo DD, Zheng JY, Wu YA
Expression of KLF6-SV2 in colorectal cancer and its impact on proliferation and apoptosis.
Eur J Cancer Prev. 2018; 27(1):20-26 [PubMed] Free Access to Full Article Related Publications
Kruppel like factor 6 (KLF6), a member of KLF family, which has classic zinc finger structure, is broadly considered to have anticancer activity. The role of SV2 variant, one of KLF6 alternative splicing isoforms has not yet been definite in the colorectal cancer. This study aimed to detect the expression of the KLF6-SV2 in colorectal cancer and investigate its impact on cell proliferation and apoptosis. qRT-PCR was used to quantitatively determine KLF6-SV2 mRNA expression in colorectal cancer samples, corresponding normal tissue, normal colonic mucosal cell line FHC and seven colorectal cancer cell lines. SW480 and SW620 cell models with over-expressing KLF6-SV2 were constructed. Cell proliferation, cell cycle and apoptosis were measured respectively using MTT assay, DNA ploidy detection and Annexin V flow cytometry. Meanwhile, expression of p53, p21 and Bax were detected by qRT-PCR and western blot. The mRNA expression level of KLF6-SV2 in colorectal cancer tissues (0.783±0.409) was decreased than in corresponding normal tissues (1.086±0.449) (P<0.01), and expression in SW480 and SW620 were lower than in FHC, HCT116, LoVo, HT29, Caco-2 and RKO. In cell lines over-expressing KLF6-SV2, cell proliferation was markedly suppressed, cell cycle was blocked and cell apoptosis was significantly induced. Simultaneously, expression of p21 and Bax were remarkably up-regulated, while p53 remained unchanged. Decreased expression of KLF6-SV2 may be associated with the occurrence and development of colorectal cancer. KLF6-SV2 plays a role as tumor suppressor by efficiently blocking cell proliferation, arresting cell cycle and inducing apoptosis in colorectal cancer, which may be related to increased expression of p21 and Bax.

Lei Z, Ma X, Li H, et al.
Up-regulation of miR-181a in clear cell renal cell carcinoma is associated with lower KLF6 expression, enhanced cell proliferation, accelerated cell cycle transition, and diminished apoptosis.
Urol Oncol. 2018; 36(3):93.e23-93.e37 [PubMed] Related Publications
OBJECTIVES: Dysregulated expression of miR-181a accompanies tumorigenesis in many human cancers. However, in clear cell renal cell carcinoma (ccRCC), the role of miR-181a remains unclear. The aim of this study was to investigate biological functions of miR-181a and its expression levels in ccRCC tissues and cancer cell lines.
MATERIAL AND METHODS: Expression levels of miR-181a in samples of ccRCC tumors and adjacent nontumor tissues from 42 patients as well as in 786-O, 769-P, A498, and CAKI-1 ccRCC cell lines were determined by quantitative real-time polymerase chain reaction. Potential targets of miR-181a were predicted using bioinformatic approaches and then verified by using the luciferase reporter assay. The effects of miR-181a on cell proliferation, colony formation, cell cycle progression, and apoptosis were investigated in ccRCC cell lines transfected with specific miR-181a mimic and inhibitor.
RESULTS: We found that miR-181a expression was up-regulated in ccRCC tissues and cell lines. The expression level of miR-181a significantly correlated with the tumor size, tumor/node/metastasis staging, and Fuhrman grade. Luciferase assays showed that KLF6 was a target of miR-181a. KLF6 expression was inversely correlated with the level of miR-181a. Overexpression of miR-181a led to reduced KLF6 mRNA and protein levels, whereas mutations of the potential miR-181a binding sites in the KLF6 gene abrogated this inhibitory effect. Furthermore, overexpression of miR-181a promoted proliferation and G1/S cell cycle transition, as well as inhibited apoptosis by down-regulating KLF6 in ccRCC cells.
CONCLUSIONS: miR-181a is up-regulated in ccRCC and may act as a tumor promoting factor by targeting KLF6 expression. Manipulating miR-181a may provide a beneficial effect in the treatment of ccRCC.

Sydor S, Manka P, Best J, et al.
Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury.
Sci Rep. 2017; 7(1):8119 [PubMed] Free Access to Full Article Related Publications
Krüppel-like factor 6 (KLF6) is a transcription factor and tumor suppressor. We previously identified KLF6 as mediator of hepatocyte glucose and lipid homeostasis. The loss or reduction of KLF6 is linked to the progression of hepatocellular carcinoma, but its contribution to liver regeneration and repair in acute liver injury are lacking so far. Here we explore the role of KLF6 in acute liver injury models in mice, and in patients with acute liver failure (ALF). KLF6 was induced in hepatocytes in ALF, and in both acetaminophen (APAP)- and carbon tetrachloride (CCl

Hsu LS, Huang RH, Lai HW, et al.
KLF6 inhibited oral cancer migration and invasion via downregulation of mesenchymal markers and inhibition of MMP-9 activities.
Int J Med Sci. 2017; 14(6):530-535 [PubMed] Free Access to Full Article Related Publications
Krüppel-like factors can bind to specific DNA motifs and regulate various cellular functions, such as metabolism, cell proliferation, and differentiation. Krüppel-like factor 6 (KLF6), a member of this family, is downregulated in human cancers. Oral cancer is a highly prevalent type in Taiwan. Although KLF6 overexpression in human cancer cells inhibits cell proliferation, induces apoptosis, and attenuates cell migration, the effects of KLF6 on oral cancer remains poorly elucidated. This study investigated the role of KLF6 in oral cancer tumorigenesis. Immunohistochemical staining revealed that nuclear KLF6 level was significantly and inversely associated with tumor size and stages. KLF6 overexpression attenuated the migration and invasion of oral cancer SAS cells. Zymography assay demonstrated that KLF6 inhibited the activities of matrix metalloproteinase 9 (MMP-9) and weakened the expression of mesenchymal markers, such as snail, slug, and vimentin. Our study is the first to provide demonstrate that KLF6 functions as a tumor suppressor gene and prevents the metastasis of oral cancer cells.

He AD, Xie W, Song W, et al.
Platelet releasates promote the proliferation of hepatocellular carcinoma cells by suppressing the expression of KLF6.
Sci Rep. 2017; 7(1):3989 [PubMed] Free Access to Full Article Related Publications
Platelets in the primary tumor microenvironment play crucial roles in the regulation of tumor progression, but the mechanisms underlying are poorly understood. Here, we report that platelet releasates exerted a proliferative effect on hepatocellular carcinoma (HCC) cells both in vitro and in vivo. This effect depended on a reduction of KLF6 expression in HCC cells. After incubation with either platelets or platelet granule contents, SMMC.7721 and HepG2 cells exhibited significant increases in proliferation and decreases in apoptosis. However, no effect was observed when incubating cancer cells with resuspended activated platelet pellet which exhausted of releasates. Platelet releasates also increased the population of HCC cells in the S and G2/M phases of the cell cycle and reduced the cell population in the G0/G1 phase. Moreover, knocking down KLF6 expression significantly diminished the platelet-mediated enhancement of HCC growth. In addition, blocking TGF-β signaling with the TGF-β receptor inhibitor SB431542 counteracted the effect of platelets on KLF6 expression and proliferation of HCC cells. Based on these findings, we conclude that platelet releasates, especially TGF-β, promote the proliferation of SMMC.7721 and HepG2 cells by decreasing expression of KLF6. This discovery identifies a potential new therapeutic target for the prevention and treatment of hepatocellular carcinoma.

Li L, Cai S, Liu S, et al.
Bioinformatics analysis to screen the key prognostic genes in ovarian cancer.
J Ovarian Res. 2017; 10(1):27 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ovarian cancer (OC) is a gynecological oncology that has a poor prognosis and high mortality. This study is conducted to identify the key genes implicated in the prognosis of OC by bioinformatic analysis.
METHODS: Gene expression data (including 568 primary OC tissues, 17 recurrent OC tissues, and 8 adjacent normal tissues) and the relevant clinical information of OC patients were downloaded from The Cancer Genome Atlas database. After data preprocessing, cluster analysis was conducted using the ConsensusClusterPlus package in R. Using the limma package in R, differential analysis was performed to identify feature genes. Based on Kaplan-Meier (KM) survival analysis, prognostic seed genes were selected from the feature genes. After key prognostic genes were further screened by cluster analysis and KM survival analysis, they were performed functional enrichment analysis and multivariate survival analysis. Using the survival package in R, cox regression analysis was conducted for the microarray data of GSE17260 to validate the key prognostic genes.
RESULTS: A total of 3668 feature genes were obtained, among which 75 genes were identified as prognostic seed genes. Then, 25 key prognostic genes were screened, including AXL, FOS, KLF6, WDR77, DUSP1, GADD45B, and SLIT3. Especially, AXL and SLIT3 were enriched in ovulation cycle. Multivariate survival analysis showed that the key prognostic genes could effectively differentiate the samples and were significantly associated with prognosis. Additionally, GSE17260 confirmed that the key prognostic genes were associated with the prognosis of OC.
CONCLUSION: AXL, FOS, KLF6, WDR77, DUSP1, GADD45B, and SLIT3 might affect the prognosis of OC.

Islam F, Gopalan V, Law S, et al.
MiR-498 in esophageal squamous cell carcinoma: clinicopathological impacts and functional interactions.
Hum Pathol. 2017; 62:141-151 [PubMed] Related Publications
MicroRNA-498 plays a crucial role in progression of many carcinomas. The signaling pathways by which miR-498 modulates carcinogenesis are still unknown. Also, miR-498-associated molecular pathogenesis has never been studied in esophageal squamous cell carcinoma (ESCC). Herein, we aimed to examine the expression and functional roles of miR-498 in ESCC as well as its influences on the clinicopathological features in patients with ESCC. Expression of miR-498 was investigated in 93 ESCC tissues and 5 ESCC cell lines using quantitative real-time polymerase chain reaction. In vitro effects of miR-498 on cellular process were studied followed by overexpression of miR-498. Western blot and immunofluorescence techniques were used to identify the interacting targets for miR-498 in ESCC. miR-498 expression was significantly reduced in ESCC when compared with the nonneoplastic esophageal tissues (P<.05). Patients with low miR-498 expression showed different histological grading of cancer and survival rates when compared with the patients with high miR-498 expression. Overexpression of miR-498 in ESCC cell lines induced remarkable reductions of cell proliferation, barrier penetration, and colony formation when compared with control and wild-type counterparts. Also, miR-498 activated the FOXO1/KLF6 transcriptional axis in ESCC. In addition, miR-498 overexpression increased p21 protein expression and led to reduced cancer cell growth. To conclude, reduced expression of miR-498 in ESCC and in vitro analysis have confirmed the tumor suppressor properties of miR-498 by modulating the FOXO1/KLF6 signaling pathway. The changes in miR-498 expression may have impacts on the clinical pathological parameters of ESCC as well as in the management of the patients with ESCC.

Masilamani AP, Ferrarese R, Kling E, et al.
KLF6 depletion promotes NF-κB signaling in glioblastoma.
Oncogene. 2017; 36(25):3562-3575 [PubMed] Free Access to Full Article Related Publications
Dysregulation of the NF-κB transcription factor occurs in many cancer types. Krüppel-like family of transcription factors (KLFs) regulate the expression of genes involved in cell proliferation, differentiation and survival. Here, we report a new mechanism of NF-κB activation in glioblastoma through depletion of the KLF6 tumor suppressor. We show that KLF6 transactivates multiple genes negatively controlling the NF-κB pathway and consequently reduces NF-κB nuclear localization and downregulates NF-κB targets. Reconstitution of KLF6 attenuates their malignant phenotype and induces neural-like differentiation and senescence, consistent with NF-κB pathway inhibition. KLF6 is heterozygously deleted in 74.5% of the analyzed glioblastomas and predicts unfavorable patient prognosis suggesting that haploinsufficiency is a clinically relevant means of evading KLF6-dependent regulation of NF-κB. Together, our study identifies a new mechanism by which KLF6 regulates NF-κB signaling, and how this mechanism is circumvented in glioblastoma through KLF6 loss.

Gao Y, Li H, Ma X, et al.
KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1.
Cancer Res. 2017; 77(2):330-342 [PubMed] Related Publications
The transcription factor KLF6 has an essential role in the development and metastasis of multiple human cancers. Paradoxically, KLF6 expression was found to be attenuated in primary metastatic clear cell renal cell carcinoma (ccRCC), such that it is unclear how KLF6 affects malignant progression in this setting. In this study, we demonstrate that KLF6 attenuation in renal cells is sufficient to promote E2F1-mediated epithelial-mesenchymal transition and metastatic prowess. In a mouse xenograft model of human ccRCC, silencing KLF6 increased tumor cell proliferation and malignant character, whereas E2F1 silencing reversed these properties. These effects were corroborated in a metastatic model system, where we observed a greater number of pulmonary metastatic lesions formed by ccRCC cells where KLF6 was silenced and E2F1 enforced. Analysis of clinical specimens of ccRCC revealed that low levels of KLF6 and high levels of E2F1 correlated closely with ccRCC development. Overall, our results established the significance of activating the KLF6-E2F1 axis in aggressive ccRCC, defining a novel critical signaling mechanism that drives human ccRCC invasion and metastasis. Cancer Res; 77(2); 330-42. ©2016 AACR.

Raninga PV, Di Trapani G, Vuckovic S, Tonissen KF
Targeted knockdown of DJ-1 induces multiple myeloma cell death via KLF6 upregulation.
Apoptosis. 2016; 21(12):1422-1437 [PubMed] Related Publications
Multiple myeloma (MM) is an incurable plasma B cell malignancy. Despite recent advancements in anti-MM therapies, development of drug resistance remains a major clinical hurdle. DJ-1, a Parkinson's disease-associated protein, is upregulated in many cancers and its knockdown suppresses tumor growth and overcomes chemoresistance. However, the role of DJ-1 in MM remains unknown. Using gene expression databases we found increased DJ-1 expression in MM patient cells, which correlated with shorter overall survival and poor prognosis in MM patients. Targeted DJ-1 knockdown using siRNAs induced necroptosis in myeloma cells. We found that Krüppel-like factor 6 (KLF6) is expressed at lower levels in myeloma cells compared to PBMCs, and DJ-1 knockdown increased KLF6 expression in myeloma cells. Targeted knockdown of KLF6 expression in DJ-1 knockdown myeloma cells rescued these cells from undergoing cell death. Higher DJ-1 levels were observed in bortezomib-resistant myeloma cells compared to parent cells, and siRNA-mediated DJ-1 knockdown reversed bortezomib resistance. DJ-1 knockdown increased KLF6 expression in bortezomib-resistant myeloma cells, and subsequent siRNA-mediated KLF6 knockdown rescued bortezomib-resistant myeloma cells from undergoing cell death. We also demonstrated that specific siRNA-mediated DJ-1 knockdown reduced myeloma cell growth under a hypoxic microenvironment. DJ-1 knockdown reduced the expression of HIF-1α and its target genes in hypoxic-myeloma cells, and overcame hypoxia-induced bortezomib resistance. Our findings demonstrate that elevated DJ-1 levels correlate with myeloma cell survival and acquisition of bortezomib resistance. Thus, we propose that inhibiting DJ-1 may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM patients.

Zhang D, Li Z, Zhang Y, et al.
miR-4262 promotes the proliferation of human cutaneous malignant melanoma cells through KLF6-mediated EGFR inactivation and p21 upregulation.
Oncol Rep. 2016; 36(6):3657-3663 [PubMed] Related Publications
Alterations in the levels and functions of microRNAs (miRs) have been associated with carcinogenesis. In this study, we investigated the role and underlying mechanism of miR-4262 in the proliferation of human cutaneous malignant melanoma (CMM) cells. The expression levels of miR-4262 were significantly upregulated in cancerous tissues compared with those in matched adjacent normal tissues from 110 CMM patients. miR-4262 was also regulated in five types of CMM cell lines, displaying an opposite expression pattern to that of Kruppel-like 6 (KLF6), a proven tumor suppressor in several cancers other than CMM. KLF6 overexpression sharply reduced A375 cell proliferation, suppressed the activation of epidermal growth factor receptor (EGFR) and increased p21 expression levels, while knockdown of KLF6 by siRNA transfection had an opposite effect. Furthermore, KLF6 was proven to be a direct target gene of miR-4262 by bioinformatic analysis and KLF6‑3'UTR luciferase reporter assay. Finally, our data on miR-4262 mimic and inhibitor transfection indicated that miR-4262 could markedly reduce the expression of KLF6 protein and had a stimulatory effect on A375 cell proliferation. Our findings indicate that KLF6 acts as a tumor suppressor in CMM cells and miR-4262 promotes the proliferation of CMM cells through KLF6-mediated EGFR inactivation and p21 upregulation.

Wang K, Ren Y, Liu Y, et al.
miR-4262 Promotes Proliferation and Invasion of Human Breast Cancer Cells Through Directly Targeting KLF6 and KLF15.
Oncol Res. 2017; 25(2):277-283 [PubMed] Related Publications
miRNAs have been shown to be involved in breast cancer growth and progression. miR-4262 is a potential tumor promoter in human cancers. In this study, we first investigated the role of miR-4262 in the proliferation and invasion of human breast cancer cells. Our results showed that, compared with the adjacent tissues and MCF-10A normal breast epithelial cells, miR-4262 was markedly increased in the breast cancer tissues and five cell lines, including MDA-MB-231, MDA-MB-468, MDA-MB-435, SKBR3, and MCF-7. Then the miR-4262 mimic or oligo anta-miR-4262 was transfected into MDA-MB-231 and MCF-7 breast cancer cell lines. The results showed that the miR-4262 mimic greatly increased the miR-4262 level and the proliferation and invasion of MDA-MB-231 and MCF-7 cells. In contrast, the anta-miR-4262 had a completely opposite effect on miR-4262 expression, cell proliferation, and cell invasion in MDA-MB-231 and MCF-7 cells. Moreover, bioinformatics and luciferase reporter gene assays confirmed that miR-4262 targeted the mRNA 3'-UTR region of KLF6 and KLF15, two characterized tumor suppressor genes. miR-4262 suppressed protein levels of KLF6 and KLF15 in MDA-MB-231 cells, and the suppression could be rescued by the transfection of pcDNA-KLF6 and -KLF15. In conclusion, miR-4262 positively regulates proliferation and invasion of human breast cancer cells via suppression of KLF6 and KLF15.

Wen PH, Wang DY, Zhang JK, et al.
Kruppel-like factor 6 suppresses growth and invasion of hepatocellular carcinoma cells in vitro and in vivo.
Int J Immunopathol Pharmacol. 2016; 29(4):666-675 [PubMed] Free Access to Full Article Related Publications
Kruppel-like factor 6 (KLF6) as a novel tumor suppressive gene participates in multiple biological behaviors and plays an important role in regulating tumor cell growth and invasion. However, the functions of KLF6 in hepatocellular carcinoma (HCC) remain poorly understood. The expression level of KLF6 was examined by immunohistochemical assay in human HCC tissues, and KLF6-overexpressed HCC cells (SMCC-7721 and HepG2) were used for evaluating cell proliferation and invasion by MTT and Transwell assays. A subcutaneous HCC tumor model was established for assessing tumor growth in vivo. Our results showed that the expression of KLF6 was significantly downregulated in HCC tissues compared with the adjacent non-cancerous tissues (50.0% vs. 72.0%, P = 0.034) and negatively associated with the lymph-vascular space invasion (LVSI) in HCC patients (P = 0.003). Furthermore, overexpression of KLF6 reduced cell proliferation and weakened the cell invasive potential followed with the decreased expression of PCNA and MMP-9 in HCC cells. The in vivo experiment indicated that KLF6 overexpression suppressed the xenograft tumor growth. Therefore, our findings show that KLF6 suppresses growth and invasion of HCC cells in vitro and in vivo, suggesting a tumor suppressive function in HCC and provides the potential therapeutic target for the treatment of HCC.

Gao X, Zhang Y, Breitling LP, Brenner H
Tobacco smoking and methylation of genes related to lung cancer development.
Oncotarget. 2016; 7(37):59017-59028 [PubMed] Free Access to Full Article Related Publications
Lung cancer is a leading cause of cancer-related mortality worldwide, and cigarette smoking is the major environmental hazard for its development. This study intended to examine whether smoking could alter methylation of genes at lung cancer risk loci identified by genome-wide association studies (GWASs). By systematic literature review, we selected 75 genomic candidate regions based on 120 single-nucleotide polymorphisms (SNPs). DNA methylation levels of 2854 corresponding cytosine-phosphate-guanine (CpG) candidates in whole blood samples were measured by the Illumina Infinium Human Methylation450 Beadchip array in two independent subsamples of the ESTHER study. After correction for multiple testing, we successfully confirmed associations with smoking for one previously identified CpG site within the KLF6 gene and identified 12 novel sites located in 7 genes: STK32A, TERT, MSH5, ACTA2, GATA3, VTI1A and CHRNA5 (FDR <0.05). Current smoking was linked to a 0.74% to 2.4% decrease of DNA methylation compared to never smoking in 11 loci, and all but one showed significant associations (FDR <0.05) with life-time cumulative smoking (pack-years). In conclusion, our study demonstrates the impact of tobacco smoking on DNA methylation of lung cancer related genes, which may indicate that lung cancer susceptibility genes might be regulated by methylation changes in response to smoking. Nevertheless, this mechanism warrants further exploration in future epigenetic and biomarker studies.

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.

Kong LM, Yao L, Lu N, et al.
Interaction of KLF6 and Sp1 regulates basigin-2 expression mediated proliferation, invasion and metastasis in hepatocellular carcinoma.
Oncotarget. 2016; 7(19):27975-87 [PubMed] Free Access to Full Article Related Publications
Accumulating evidence suggests that the tumor suppressor gene Krüppel-like factor 6 (KLF6) plays important roles in both development and progression of cancer. However, the role of KLF6 in hepatocellular carcinoma (HCC) remains unclear. Cancer-related molecule basigin-2 plays an important role in HCC progression and metastasis. Sp1, one of Sp/KLFs family members, regulates basigin-2 expression in HCC. The involvement of KLFs in basigin-2 regulation and HCC progression and metastasis has not been investigated. We first measured KLF6 expression levels in 50 pairs of HCC and adjacent normal tissues (ANTs) by immunohistochemistry. Specifically, low KLF6 expression but high Sp1 and basigin-2 expression were found in HCC tissues. By contrast, the ANTs showed high KLF6 expression but low Sp1 and basigin-2 expression. Kaplan-Meier analysis showed that higher expression of KLF6 was associated with better overall survival. The survival rate of KLF6-negative patients was lower than that of KLF6-positive patients (P = 0.015). We also found that KLF6 binds to the basigin-2 and Sp1 promoters and decreases their expression. Thus, we identified a microcircuitry mechanism in which KLF6 can repress basigin-2 expression directly by binding to its promoter or indirectly by inhibiting the expression of the transcription factor Sp1 to block gene expression. Additionally, overexpression of KLF6 suppressed the invasion, metastasis and proliferation of HCC cells in vitro and in vivo by targeting basigin-2. Our study provides new evidence that interaction of KLF6 and Sp1 regulates basigin-2 expression in HCC and that KLF6 represses the invasive and metastatic capacities of HCC through basigin-2.

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.

Sun H, Yan L, Tu R, et al.
Expression Profiles of Endometrial Carcinoma by Integrative Analysis of TCGA Data.
Gynecol Obstet Invest. 2017; 82(1):30-38 [PubMed] Related Publications
BACKGROUND: This study was to explore the expression profile of endometrial carcinoma (EC) and identify the potential molecular mechanism and therapeutic targets.
METHODS: Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified in EC using mRNA and miRNA sequencing data released by the Cancer Genome Atlas database; then, gene function and pathway of DEGs were analyzed based on the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway databases; finally, the transcription factors (TFs) latently regulating the DEGs and DEMs were predicted and a TF-miRNA-Gene network was then established to summarize the regulatory links between TFs, DEMs and DEGs.
RESULTS: One thousand five hundred and forty two upregulated and 1,885 downregulated DEGs, 34 upregulated and 12 downregulated DEMs were identified. The principal DEGs-enriched functions were cell differentiation, cell migration, and cell surface receptor signaling pathway. The DEGs-enriched cell signaling pathways including the MAPK, Wnt signaling pathway, and the p53 signaling pathway. As shown in the TF-miRNA-Gene network, TFs such as CPBP and GKLF, miRNAs such as miR-141-3p and miR-130b-3p, regulated most of DEGs and DEMs.
CONCLUSION: These results may contribute to the study of the molecular mechanism and therapeutic targets in EC, and facilitate the discovery of new biomarkers for screening, diagnosis and monitoring.

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