Gene Summary

Gene:KLF5; Kruppel like factor 5
Aliases: CKLF, IKLF, BTEB2
Summary:This gene encodes a member of the Kruppel-like factor subfamily of zinc finger proteins. The encoded protein is a transcriptional activator that binds directly to a specific recognition motif in the promoters of target genes. This protein acts downstream of multiple different signaling pathways and is regulated by post-translational modification. It may participate in both promoting and suppressing cell proliferation. Expression of this gene may be changed in a variety of different cancers and in cardiovascular disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2013]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:Krueppel-like factor 5
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

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

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Latest Publications: KLF5 (cancer-related)

Lu Y, Kweon SS, Tanikawa C, et al.
Large-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer.
Gastroenterology. 2019; 156(5):1455-1466 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND & AIMS: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations.
METHODS: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels.
RESULTS: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10
CONCLUSIONS: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.

Yu L, Xu Q, Yu W, et al.
LncRNA cancer susceptibility candidate 15 accelerates the breast cancer cells progression via miR-153-3p/KLF5 positive feedback loop.
Biochem Biophys Res Commun. 2018; 506(4):819-825 [PubMed] Related Publications
Emerging literature have illustrated the vital regulatory roles of long noncoding RNAs (lncRNAs) on the breast cancer tumorigenesis. Although series of researches have been proceeded on the pathogenesis, there are still much of unsolved mysteries worth investigating. This study uncovered that CASC15 expression level was aberrantly high-expressed in breast cancer tissue specimens and cells. Functionally, the loss-of-functional experiments showed that knockdown of CASC15 suppressed the malignant behaviors of breast cancer cells, such as proliferation, invasion and tumor growth in vitro and vivo. Mechanically, we confirmed that CASC15 functioned as a competing endogenous RNA (ceRNA) of miR-153-3p, besides, miR-153-3p targeted the 3'-UTR of KLF5 mRNA utilizing the bioinformatics online tools, luciferase reporter assay and RNA immunoprecipitation. Interestingly, we confirmed that the transcription factor KLF5 binds with the promoter region of CASC15 and activates the transcription. In conclusion, we validated the positive feedback loop of KLF5/CASC15/miR-153-3p/KLF5 in the acceleration of breast cancer malignant behaviors and tumorigenesis, suggesting the important biologic roles of CASC15 on the breast cancer tumorigenesis.

Wu Q, Fu C, Li M, et al.
CINP is a novel cofactor of KLF5 required for its role in the promotion of cell proliferation, survival and tumor growth.
Int J Cancer. 2019; 144(3):582-594 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Krüppel-like factor 5 (KLF5) both suppresses and promotes tumor growth depending on cellular context. The mechanisms underlying tumor promotion could be targetable for therapy. Although a number of transcriptional targets of KLF5 have been identified and implicated in KLF5-mediated tumor growth, how KLF5 regulates these genes remains to be addressed. Here we performed coimmunoprecipitation (co-IP) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the TSU-Pr1 bladder cancer cell line, in which KLF5 is shown to promote tumor growth, to identify KLF5-interacting nuclear proteins that are necessary for KLF5's tumor promoting function. LC-MS/MS revealed 122 potential KLF5 binding proteins in the nuclear proteins precipitated by the KLF5 antibody, and the top nine candidates included AHNAK, TFAM, HSDL2, HNRNPC, CINP, IST1, FBL, PABPC1 and SNRNP40. SRB assays of these nine proteins indicated that silencing CINP had the most potent inhibitory effect on cell growth in KLF5-expressing cells but did not affect parental TSU-Pr1 cells. Further analyses not only confirmed the physical interaction between KLF5 and CINP, also demonstrated that knockdown of CINP attenuated the effects of KLF5 on cell cycle progression, apoptosis and tumorigenesis. Silencing CINP also attenuated the effect of KLF5 on the expression of a number of genes and signaling pathways, including cell cycle regulator Cyclin D1 and apoptosis-related Caspase 7. These results suggest that CINP is a cofactor of KLF5 that is crucial for the promotion of tumor growth, and that the KLF5-CINP interaction could be a novel therapeutic target for inhibiting KLF5-promoted tumor growth.

Ma Y, Wang Q, Liu F, et al.
KLF5 promotes the tumorigenesis and metastatic potential of thyroid cancer cells through the NF-κB signaling pathway.
Oncol Rep. 2018; 40(5):2608-2618 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
The purpose of the present study was to identify the potential function of Kruppel-like factor 5 (KLF5) in thyroid cancer and investigate the underlying mechanisms. The protein levels of KLF5 in 98 thyroid cancer tissues were analyzed using an immunohistochemistry assay. SW579 cells transfected with small interfering RNA against KLF5 and B-CPAP cells transfected with KLF5 expressing vectors were used for functional studies. Western blot analysis, immunofluorescence and co-immunoprecipitation assays were used to investigate the mechanisms of KLF5. In vivo tumorigenicity was assessed using a subcutaneous xenograft experiment. The results revealed that KLF5 was highly expressed in thyroid cancer tissues and associated with lymph node metastasis. Knockdown of KLF5 in SW579 cells suppressed proliferation, anchorage-independent growth, migration and invasion in vitro, while the overexpression of KLF5 resulted in opposite effects in B-CPAP cells. Mechanistically, it was demonstrated that KLF5 promoted the cytoplasm-nuclear translocation of nuclear factor-κB. Additionally, it was revealed that insufficient F-box/WD repeat-containing protein 7 expression may be responsible for the dysfunction of KLF5 in thyroid cancer. These results revealed that KLF5 promotes the tumorigenesis and metastasis of thyroid cancer cells and may be a potential therapeutic target in patients with thyroid cancer.

Zinovyeva MV, Nikolaev LG, Kondratyeva LG, et al.
Correlation between Expression of KLF5 and ZEB1 Transcription Factor Genes in Pancreatic Cancer.
Dokl Biochem Biophys. 2018; 481(1):219-221 [PubMed] Related Publications
The mRNA content of the transcription factors KLF5 and ZEB1 was studied in pancreatic tumor tissues and in fetal and normal pancreas. Transcription of these factors was not high and similar in normal and fetal pancreatic tissues but greatly increased in the pancreatic ductal adenocarcinoma tissues. A significant positive correlation between the KLF5 and ZEB1 transcription levels in the pancreatic tumor tissues was observed.

Zhang H, Lu Y, Wang S, et al.
MicroRNA-152 Acts as a Tumor Suppressor MicroRNA by Inhibiting Krüppel-Like Factor 5 in Human Cervical Cancer.
Oncol Res. 2019; 27(3):335-340 [PubMed] Related Publications
Aberrant expression of microRNA-152 (miR-152) is frequently observed in human cancers including ovarian cancer, breast cancer, prostate cancer, and gastric cancer. However, its expression and functional role in cervical cancer (CC) are poorly understood. Also, the association between miR-152 and Krüppel-like factor 5 (KLF5) expression in CC remains unclear. In this study, analyzing the expression of miR-152 by quantitative real-time PCR (qRT-PCR) revealed it was sharply reduced in CC tissues and cell lines. In addition, the negative correlation of miR-152 expression and KLF5 expression was observed. The dual-luciferase reporter assay validated that KLF5 was a target of miR-152. In vitro functional assays revealed that miR-152 could inhibit cell proliferation and cell cycle progression through regulating the expression of KLF5. Taken together, our study suggested that miR-152 functions as a tumor suppressor in CC, and the miR-152/KLF5 axis may provide novel therapeutic targets for CC treatment.

Li W, Qi Y, Cui X, et al.
Characteristic of HPV Integration in the Genome and Transcriptome of Cervical Cancer Tissues.
Biomed Res Int. 2018; 2018:6242173 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
High-risk HPV is clearly associated with cervical cancer. HPV integration has been confirmed to promote carcinogenesis in the previous studies. In our study, a total of 285 DNA breakpoints and 287 RNA breakpoints were collected. We analyzed the characteristic of HPV integration in the DNA and RNA samples. The results revealed that the patterns of HPV integration in RNA and DNA samples differ significantly.

Cai W, Xu Y, Yin J, et al.
miR‑590‑5p suppresses osteosarcoma cell proliferation and invasion via targeting KLF5.
Mol Med Rep. 2018; 18(2):2328-2334 [PubMed] Related Publications
Recently, microRNA (miR)‑590‑5p has been shown to inhibit tumorigenesis in colorectal and breast cancer; however, its function in osteosarcoma (OS) requires further investigation. In the present study miR‑590‑5p expression was poorly expressed in OS samples and cell lines when compared with that observed in normal cells. In addition, overexpression of miR‑590‑5p significantly reduced the proliferation, migration and invasion of SAOS2 and U2OS cells in vitro, as well as inhibiting tumor sizes in vivo. The results revealed that miR‑590‑5p directly targeted Kruppel‑like factor 5 (KLF5) in SAOS2 and U2OS cells. Their expression was inversely correlated with OS tissues. Finally, it was demonstrated that overexpression of KLF5 rescued the inhibitory effects of miR‑590‑5p on cell proliferation, migration and invasion. Overall, the results of the present study suggested that the miR‑590‑5p/KLF5 axis may regulate OS progression and thus, may be a novel therapeutic target for the treatment of patients with OS.

Gong T, Cui L, Wang H, et al.
Knockdown of KLF5 suppresses hypoxia-induced resistance to cisplatin in NSCLC cells by regulating HIF-1α-dependent glycolysis through inactivation of the PI3K/Akt/mTOR pathway.
J Transl Med. 2018; 16(1):164 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: Hypoxia-mediated chemoresistance has been regarded as an important obstacle in the development of cancer treatment. Knockdown of krüppel-like factor 5 (KLF5) was reported to inhibit hypoxia-induced cell survival and promote cell apoptosis in non-small cell lung cancer (NSCLC) cells via direct regulation of hypoxia inducible factor-1α (HIF-1α) expression. However, the roles of KLF5 in the development of hypoxia-induced cisplatin (DDP) resistance and its underlying mechanism in NSCLC cells remain to be further elucidated.
METHODS: Western blot was performed to determine the protein levels of KLF5, P-glycoprotein (P-gp) and HIF-1α in treated NSCLC cells. Cell survival was examined by MTT assay. The effect of KLF5 knockdown on hypoxia-induced glycolysis was assessed by measuring glucose consumption and lactate production. The effect of KLF5 knockdown on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway was analyzed by western blot.
RESULTS: Hypoxia upregulated the expression of KLF5 in NSCLC cells. KLF5 knockdown suppressed hypoxia-induced DDP resistance in NSCLC cells, as demonstrated by the increased cytotoxic effects of DDP and reduced P-gp expression in NSCLC cells in hypoxia. Moreover, KLF5 knockdown inhibited hypoxia-induced HIF-1α expression and glycolysis, and KLF5 knockdown suppressed hypoxia-induced DDP resistance by inhibiting HIF-1α-dependent glycolysis in NSCLC cells. Furthermore, KLF5 knockdown suppressed hypoxia-induced activation of the PI3K/Akt/mTOR pathway in NSCLC cells and KLF5 overexpression promoted hypoxia-induced DDP resistance in NSCLC cells through activation of the PI3K/Akt/mTOR pathway.
CONCLUSIONS: KLF5 knockdown could suppress hypoxia-induced DDP resistance, and its mechanism may be due to the inhibition of HIF-1α-dependent glycolysis via inactivation of the PI3K/Akt/mTOR pathway.

Liu Z, Liu X, Liu S, Cao Q
Cholesterol promotes the migration and invasion of renal carcinoma cells by regulating the KLF5/miR-27a/FBXW7 pathway.
Biochem Biophys Res Commun. 2018; 502(1):69-75 [PubMed] Related Publications
Clear cell renal cell carcinoma (ccRCC) is the most common and lethal subtype of renal cell carcinoma. Accumulation of cholesterol and cholesterol ester is a remarkable feature of ccRCC. However, the effect of cholesterol on ccRCC remains unknown. Out results showed that cholesterol treatment significantly promoted cells migration and invasion in ccRCC. Mechanism analysis indicated that cholesterol induced KLF5 expression. KLF5 positively regulated the transcription of miR-27a, increasing miR-27a expression. MiR-27a directly targeted FBXW7 by binding to its 3'UTR, reducing FBXW7 expression. FBXW7 silencing further increased the expression of KLF5 and miR-27a, and promoted cells migration and invasion. These results suggested that cholesterol accelerated ccRCC cells migration and invasion by regulating KLF5/miR-27a/FBXW7 axis.

Zhao C, Li Y, Qiu W, et al.
C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation.
Oncogene. 2018; 37(35):4821-4837 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and multiple evidence has confirmed that C5a production is elevated in NSCLC microenvironment. Although NSCLC cell proliferation induced by C5a has been reported, the involved mechanism has not been elucidated. In this study, we examined the proliferation-related genes (i.e., KLF5, GCN5, and GDF15) and C5a receptor (C5aR) expression in tumor tissues as well as C5a concentration in plasma of NSCLC patients, and then determined the roles of KLF5, GCN5, and GDF15 in C5a-triggered NSCLC cell proliferation and the related mechanism both in vitro and in vivo. Our results found that the expression of KLF5, GCN5, GDF15, C5aR, and C5a was significantly upregulated in NSCLC patients. Mechanistic exploration in vitro revealed that C5a could facilitate A549 cell proliferation through increasing KLF5, GCN5, and GDF15 expression. Besides, KLF5 and GCN5 could form a complex, binding to GDF15 promoter in a KLF5-dependent manner and leading to GDF15 gene transcription. More importantly, GCN5-mediated KLF5 acetylation contributing to GDF15 gene transcription and cell proliferation upon C5a stimulation, the region (-103 to +58 nt) of GDF15 promoter which KLF5 could bind to, and two new KLF5 lysine sites (K335 and K391) acetylated by GCN5 were identified for the first time. Furthermore, our experiment in vivo demonstrated that the growth of xenograft tumors in BALB/c nude mice was greatly suppressed by the silence of KLF5, GCN5, or GDF15. Collectively, these findings disclose that C5a-driven KLF5-GCN5-GDF15 axis had a critical role in NSCLC proliferation and might serve as targets for NSCLC therapy.

Tang J, Li Y, Sang Y, et al.
LncRNA PVT1 regulates triple-negative breast cancer through KLF5/beta-catenin signaling.
Oncogene. 2018; 37(34):4723-4734 [PubMed] Related Publications
ABSTACT: Recent molecularly targeted approach gains advance in breast cancer treatment. However, the estimated 5-year survival rate has not met the desired expectation for improvement, especially for patients with triple-negative breast cancer (TNBC). Here we report that the lncRNA PVT1 promotes KLF5/beta-catenin signaling to drive TNBC tumorigenesis. PVT1 is upregulated in clinical TNBC tumors. Using genetic approaches targeting PVT1 in TNBC cells, we found that PVT1 depletion inhibited cell proliferation, colony formation, and orthotopic xenograft tumor growth. Mechanistically, PVT1 binds with KLF5 and increases its stability via BAP1, which upregulates beta-catenin signaling, resulting in enhanced TNBC tumorigenesis. PVT1, KLF5, and beta-catenin were also revealed to be co-expressed in clinical TNBC samples. Our findings uncover a new singaling pathway to mediate TNBC, and provide PVT1 as a new target for improving treatment of TNBC.

Liang H, Sun H, Yang J, Yi C
miR‑145‑5p reduces proliferation and migration of hepatocellular carcinoma by targeting KLF5.
Mol Med Rep. 2018; 17(6):8332-8338 [PubMed] Related Publications
MicroRNAs (miRs) are important in hepatocellular carcinoma (HCC) progression. miR‑145‑5p acts as a tumor suppressor in certain malignancies, however, its role in HCC remains unclear. The present study aimed to perform a functional analysis of miR‑145‑5p in HCC in order to elucidate its role in the pathogenesis of HCC. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was performed to analyze tissue and cellular expression of miR‑145‑5p in HCC. Following miRNA mimics transfection, cell viability, apoptosis and cells migration were determined by Cell Counting kit‑8, Annexin V‑FITC/propidium iodide staining and Transwell analyses. The target of miR‑145‑5p was analyzed by luciferase reporter assay and western blot analysis. It was observed that miR‑145‑5p was significantly decreased in HCC tissues and cell lines. Overexpression of miR‑145‑5p significantly increased apoptosis, reduced cell proliferation and suppressed HCC cell migration. Kruppel‑like factor 5 (KLF5) is regarded as a target of miR‑145‑5p in HCC cells. In addition, KLF5 overexpression partially attenuated the tumor suppressive effects of miR‑145‑5p. KLF5 expression was negatively associated with levels of miR‑145‑5p in HCC tissues. The present study demonstrated that miRNA‑145‑5p may, by targeting KLF5, partially suppress HCC cell growth and motility. The results of the present study suggested that miRNA‑145‑5p alteration in HCC may serve a role in the progression of HCC.

Tanikawa C, Kamatani Y, Takahashi A, et al.
GWAS identifies two novel colorectal cancer loci at 16q24.1 and 20q13.12.
Carcinogenesis. 2018; 39(5):652-660 [PubMed] Related Publications
Colorectal cancer (CRC) is the fourth leading cause of cancer mortality worldwide. Genome-wide association studies (GWAS) identified more than 50 CRC loci. However, most of the previous studies were conducted in European population, and host genetic factors among Japanese population are largely remained to be identified. To identify novel loci in the Japanese population, here, we performed a large-scale GWAS using 6692 cases and 27 178 controls followed by a replication analysis using more than 11 000 case-control samples. We found the significant association of 10 loci (P < 5 × 10-8), including 2 novel loci on 16q24.1 (IRF8-FOXF1, rs847208, P = 3.15 × 10-9 and odds ratio = 1.107 with 95% confidence interval (CI) of 1.071-1.145) and 20q13.12 (TOX2, rs6065668, P = 4.47 × 10-11 and odds ratio = 0.897 with 95% CI of 0.868-0.926). Moreover, 35 previously reported single nucleotide polymorphisms (SNPs) in 24 regions were validated in the Japanese population (P < 0.05) with the same risk allele as in the previous studies. SNP rs6065668 was significantly associated with TOX2 expression in the sigmoid colon. In addition, nucleotide substitutions in the regulatory region of TOX2 were predicted to alter the binding of several transcription factors, including KLF5. Our findings elucidate the important role of genetic variations in the development of CRC in the Japanese population.

Liu R, Zhi X, Zhou Z, et al.
Mithramycin A suppresses basal triple-negative breast cancer cell survival partially via down-regulating Krüppel-like factor 5 transcription by Sp1.
Sci Rep. 2018; 8(1):1138 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
As the most malignant breast cancer subtype, triple-negative breast cancer (TNBC) does not have effective targeted therapies clinically to date. As a selective Sp1 inhibitor, Mithramycin A (MIT) has been reported to have anti-tumor activities in multiple cancers. However, the efficacy and the mechanism of MIT in breast cancer, especially TNBC, have not been studied. In this study, we demonstrated that MIT suppressed breast cancer cell survival in a dosage-dependent manner. Interestingly, TNBC cells were more sensitive to MIT than non-TNBC cells. MIT inhibited TNBC cell proliferation and promoted apoptosis in vitro in time- and dosage-dependent manners. MIT suppressed TNBC cell survival, at least partially, by transcriptionally down-regulating KLF5, an oncogenic transcription factor specifically expressed in basal TNBC. Finally, MIT suppressed TNBC cell growth in a xenograft mouse model. Taken together, our findings suggested that MIT inhibits basal TNBC via the Sp1/KLF5 axis and that MIT may be used for TNBC treatment.

Lu M, Huang Y, Sun W, et al.
miR-135b-5p promotes gastric cancer progression by targeting CMTM3.
Int J Oncol. 2018; 52(2):589-598 [PubMed] Related Publications
CKLF-like MARVEL transmembrane domain containing 3 (CMTM3) is considered to be a tumor suppressor gene in multiple types of malignancies. Previous studies have indicated that CMTM3 suppresses metastasis and epithelial-mesenchymal transition (EMT) in gastric cancer. However, its role in gastric cancer cell proliferation has rarely been discussed. Moreover, the regulatory mechanisms of CMTM3 in gastric cancer remain unclear. In this study, RT‑qPCR and IHC were used to assess the expression of CMTM3 and miR‑135b‑5p in gastric cancer tissues and cell lines. We found that the expression of miR‑135b‑5p was negatively associated with CMTM3 in gastric cancer tissues, and we verified that miR‑135b‑5p directly targeted CMTM3 in gastric cancer cells by dual-luciferase reporter assay. CCK8 assay, Transwell assay and flow cytometric analysis were conducted to examine the functions of CMTM3 and miR‑135b‑5p in vitro. Our results demonstrated that the overexpression of CMTM3 or the suppression of miR‑135b‑5p using an inhibitor suppressed SGC‑7901 gastric cancer cell proliferation, invasion and cell cycle progression, and promoted SGC‑7901 cell apoptosis. Furthermore, a BALB/c nude mouse subcutaneous xenograft model was used to verify the function of miR‑135b‑5p and CMTM3. Our results revealed that miR‑135b‑5p inhibitor significantly suppressed SGC‑7901 cell tumorigenesis in vivo. In addition, IHC revealed that CMTM3 expression was markedly increased in tumors infected with miR‑135b‑5p inhibitor lentivirus. On the whole, the findings of the present study suggest that the overexpression of miR‑135b‑5p inhibits CMTM3 expression, and promotes gastric cancer progression and metastasis. Our findings provide a novel therapeutic target for gastric cancer.

Hasegawa T, Glavich GJ, Pahuski M, et al.
Characterization and Evidence of the miR-888 Cluster as a Novel Cancer Network in Prostate.
Mol Cancer Res. 2018; 16(4):669-681 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Prostate cancer afflicts 1 in 7 men and is the second leading cause of male cancer-related deaths in the United States. MicroRNAs (miRNAs), an extensive class of approximately 22 nucleotide noncoding RNAs, are often aberrantly expressed in tissues and fluids from prostate cancer patients, but the mechanisms of how specific miRNAs regulate prostate tumorigenesis and metastasis are poorly understood. Here, miR-888 was identified as a novel prostate factor that promotes proliferation and migration. miR-888 resides within a genomic cluster of 7 miRNA genes (

He P, Yang JW, Yang VW, Bialkowska AB
Krüppel-like Factor 5, Increased in Pancreatic Ductal Adenocarcinoma, Promotes Proliferation, Acinar-to-Ductal Metaplasia, Pancreatic Intraepithelial Neoplasia, and Tumor Growth in Mice.
Gastroenterology. 2018; 154(5):1494-1508.e13 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND & AIMS: Activating mutations in KRAS are detected in most pancreatic ductal adenocarcinomas (PDACs). Expression of an activated form of KRAS (KrasG12D) in pancreata of mice is sufficient to induce formation of pancreatic intraepithelial neoplasia (PanINs)-a precursor of PDAC. Pancreatitis increases formation of PanINs in mice that express KrasG12D by promoting acinar-to-ductal metaplasia (ADM). We investigated the role of the transcription factor Krüppel-like factor 5 (KLF5) in ADM and KRAS-mediated formation of PanINs.
METHODS: We performed studies in adult mice with conditional disruption of Klf5 (Klf5
RESULTS: Of the 96 PDAC samples analyzed, 73% were positive for KLF5 (defined as nuclear staining in more than 5% of tumor cells). Pancreata from Ptf1a-Cre
CONCLUSION: Levels of KLF5 are increased in human PDAC samples and in PanINs of Ptf1a-Cre

Ma D, Chang LY, Zhao S, et al.
KLF5 promotes cervical cancer proliferation, migration and invasion in a manner partly dependent on TNFRSF11a expression.
Sci Rep. 2017; 7(1):15683 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Although the transcription factor Krüppel-like factor 5 (KLF5) plays important roles in both inflammation and cancer, the mechanism by which this factor promotes cervical carcinogenesis remains unclear. In this study, we demonstrated a potential role for tumour necrosis factor receptor superfamily member 11a (TNFRSF11a), the corresponding gene of which is a direct binding target of KLF5, in tumour cell proliferation and invasiveness. Coexpression of KLF5 and TNFRSF11a correlated significantly with tumorigenesis in cervical tissues (P < 0.05) and manipulation of KLF5 expression positively affected TNFRSF11a mRNA and protein expression. Functionally, KLF5 promoted cancer cell proliferation, migration and invasiveness in a manner dependent partly on TNFRSF11a expression. Moreover, in vivo functional TNFRSF11a-knockdown mouse studies revealed suppression of tumorigenicity and liver metastatic potential. Notably, tumour necrosis factor (TNF)-α induced KLF5 expression by activating the p38 signalling pathway and high KLF5 and TNFRSF11a expression increased the risk of death in patients with cervical squamous cell carcinoma. Our results demonstrate that KLF5 and TNFRSF11a promote cervical cancer cell proliferation, migration and invasiveness.

Abjalimov IR, Zinovyeva MV, Nikolaev LG, et al.
Expression of transcription factor genes in cell lines corresponding to different stages of pancreatic cancer progression.
Dokl Biochem Biophys. 2017; 475(1):267-270 [PubMed] Related Publications
The expression level of six transcription factor genes and the content of their protein products in five pancreatic cancer cell lines with parallel control of expression of three marker genes reflecting epithelial or mesenchymal state of cells was investigated. Cell lines MIA PaCa-2 and Capan-2 represented the best models of quasi-mesenchymal and epithelial, respectively, types of progression of the pancreatic ductal adenocarcinoma, according to the content of E-cadherin and vimentin and the expression of KLF5 and ZEB1 transcription factors.

Kondratyeva LG, Chernov IP, Zinovyeva MV, et al.
Expression of master regulatory genes of embryonic development in pancreatic tumors.
Dokl Biochem Biophys. 2017; 475(1):250-252 [PubMed] Related Publications
The expression level of some important master regulators of embryonic development of the pancreas in the tumor samples of this human organ was determined. We found that the transcription of SOX9, GATA4, PDX1, PTF1a, and HNF1b genes in the tumor samples was reduced as compared to the samples of normal pancreatic tissues, and the KLF5 gene expression in the tumor cells was elevated. We assume that all the studied genes, except KLF5, form a single regulatory module that supports the identity of tumor progenitor cells. A simultaneous suppression of expression of these master factors may be critical for the neoplastic transformation of pancreatic cells.

Kondratyeva LG, Didych DA, Chernov IP, et al.
Dependence of expression of regulatory master genes of embryonic development in pancreatic cancer cells on the intracellular concentration of the master regulator PDX1.
Dokl Biochem Biophys. 2017; 475(1):259-263 [PubMed] Related Publications
Exogenous expression of the gene encoding the pancreatic master regulator PDX1 in cell lines with different degrees of differentiation of pancreatic cancer cells is accompanied by changes in the expression of known master genes involved in cancer progression. In BxPC3

Fu RJ, He W, Wang XB, et al.
DNMT1-maintained hypermethylation of Krüppel-like factor 5 involves in the progression of clear cell renal cell carcinoma.
Cell Death Dis. 2017; 8(7):e2952 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Clear cell renal cell carcinoma (ccRCC) is the major subtype of renal cell carcinoma (RCC) that is resistant to conventional radiation and chemotherapy. It is a challenge to explore effective therapeutic targets and drugs for this kind of cancer. Transcription factor Krüppel-like factor 5 (KLF5) exerts diverse functions in various tumor types. By analyzing cohorts of the Cancer Genome Atlas (TCGA) data sets, we find that KLF5 expression is suppressed in ccRCC patients and higher level of KLF5 expression is associated with better prognostic outcome. Our further investigations demonstrate that KLF5 genomic loci are hypermethylated at proximal exon 4 and suppression of DNA methyltransferase 1 (DNMT1) expression by ShRNAs or a methylation inhibitor 5-Aza-CdR can recover KLF5 expression. Meanwhile, there is a negative correlation between expressions of KLF5 and DNMT1 in ccRCC tissues. Ectopic KLF5 expression inhibits ccRCC cell proliferation and migration/invasion in vitro and decreases xenograft growth and metastasis in vivo. Moreover, 5-Aza-CdR, a chemotherapy drug as DNMTs' inhibitor that can induce KLF5 expression, suppresses ccRCC cell growth, while knockdown of KLF5 abolishes 5-Aza-CdR-induced growth inhibition. Collectively, our data demonstrate that KLF5 inhibits ccRCC growth as a tumor suppressor and highlight the potential of 5-Aza-CdR to release KLF5 expression as a therapeutic modality for the treatment of ccRCC.

Souza TM, van den Beucken T, Kleinjans JCS, Jennen DGJ
Inferring transcription factor activity from microarray data reveals novel targets for toxicological investigations.
Toxicology. 2017; 389:101-107 [PubMed] Related Publications
Transcription factors (TFs) are important modulators of the inducible portion of the transcriptome, and therefore relevant in the context of exposure to exogenous compounds. Current approaches to predict the activity of TFs in biological systems are usually restricted to a few entities at a time due to low-throughput techniques targeting a limited fraction of annotated human TFs. Therefore, high-throughput alternatives may help to identify new targets of mechanistic and predictive value in toxicological investigations. In this study, we inferred the activity multiple TFs using publicly available microarray data from primary human hepatocytes exposed to hundreds of chemicals and evaluated these molecular profiles using multiple correspondence analysis. Our results demonstrate that the lowest dose and latest exposure time (24h) in a subset of chemicals generates a signature indicative of carcinogenicity possibly due to DNA-damaging properties. Furthermore, profiles from the earliest exposure time (2h) and highest dose creates clusters of chemicals implicated in the development of diverse forms of drug-induced liver injury (DILI). Both approaches yielded a number of TFs with similar activity across groups of chemicals, including TFs known in toxicological responses such as AhR, NFE2L2 (Nrf2), NF-κB and PPARG. FOXM1, IRF1 and E2F4 were some of the TFs identified that may be relevant in genotoxic carcinogenesis. SMADs (SMAD1, SMAD2, SMAD5) and KLF5 were identified as some of potentially new TFs whose inferred activities were linked to acute and progressive outcomes in DILI. In conclusion this study offers a novel mechanistic approach targeting TF activity during chemical exposure.

Chang L, Ma D, Li O, et al.
Expressions and Functions of Krüppel Like Factor 5 and Tumor Necrosis Factor Receptor Superfamily Member 11a in Cervical Cancer Tissues and Cells.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2017; 39(2):196-205 [PubMed] Related Publications
Objective To investigate the expressions of Krüppel like factor 5 (KLF5) and tumor necrosis factor receptor superfamily member 11a (TNFRSF11a) in cervical cancer tissues and their effect on proliferation,migration,and invasion of HeLa cells. Methods Microarray technology was used to detect the mRNA expression of gene in cytocine stimulusin cervical tissues,and the result was verified by real-time fluorescence quantitative polymerase chain reaction. The expressions of KLF5 and TNFRSF11a in cervical tissues were detected by double immunofluorescence staining. HeLa cells were transfected with specific small interfering RNA to knock down the endogenous TNFRSF11a and KLF5 and were infected with adenovirus containing KLF5 to over-express KLF5,respectively. Protein level was detected by Western blot. The regulatory effect of KLF5 on candidate target gene (TNFRSF11a) was determined by dual-luciferase reporter assay. The activity of the cell proliferation,migration,and invasion was detected by using cell counting kit-8 assay and Transwell assay. Results The results of microarray technology showed that the expressions of KLF5 and TNFRSF11a were significantly higher in cervical squamous cell carcinoma tissues compared with normal cervical tissues (P=0.002,P=0.045),and real-time fluorescence quantitative polymerase chain reaction showed that the mRNA expressions of KLF5 and TNFRSF11a were significantly higher in cervical intraepithelial neoplasia (CIN) Ⅰ,CINⅡ-Ⅲ and cervical squamous cell carcinoma tissues compared with normal cervical tissues (KLF5:F=32.79,P=0.018,P=0.014,and P=0.011;TNFRSF11a:F=36.72,P=0.013,P=0.010,and P=0.009) and double immunofluorescence staining showed that the protein expressions of KLF5 and TNFRSF11a were significantly higher in CIN Ⅰ,CIN Ⅱ-Ⅲ and cervical squamous cell carcinoma tissues compared with normal cervical tissues (KLF5:F=42.38,P=0.014,P=0.008,and P=0.002;TNFRSF11a:F=35.42,P=0.021,P=0.012,and P=0.004) and increased with the carcinogenesis. The experiment in vitro confirmed that KLF5 promotes proliferation,migration,and invasion of HeLa by up-regulating TNFRSF11a expression. Clinical analysis showed that the expression of TNFRSF11a mRNA was positively correlated with tumor pathological grading,clinical stage,depth of invasion,and lymph node metastasis (all P<0.05). Conclusion KLF5 and TNFRSF11a are related to cervical cancer. KLF5 promote the proliferation,migration,and invasion of cervical cancer cells partly by upregulating the transcription of TNFRSF11a.

Zhou W, Song F, Wu Q, et al.
miR-217 inhibits triple-negative breast cancer cell growth, migration, and invasion through targeting KLF5.
PLoS One. 2017; 12(4):e0176395 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Triple negative breast cancer (TNBC) is one of the most aggressive breast cancers without effective targeted therapies. Numerous studies have implied that KLF5 plays an important roles in TNBC. How is KLF5 regulated by microRNAs has not been well studied. Here, we demonstrated that miR-217 down-regulates the expression of KLF5 and KLF5's downstream target gene FGF-BP and Cyclin D1 in TNBC cell lines HCC1806 and HCC1937. Consequently, miR-217 suppresses TNBC cell growth, migration, and invasion. MiR-217 suppresses TNBC, at least partially, through down-regulating the KLF5 expression. These results suggest that the miR-217-KLF5 axis might serve as a potential target for treatment of TNBC.

Hoskins JW, Ibrahim A, Emmanuel MA, et al.
Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression.
Hum Mol Genet. 2016; 25(21):4726-4738 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610 kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3 and BORA, range in distance from 265-586 kb. Sequencing three sub-regions containing the top ranked SNPs by imputation P-value revealed a 30 bp insertion/deletion (indel) variant that was significantly associated with pancreatic cancer risk (rs386772267, P = 2.30 × 10

Jiang Z, Zhang Y, Cao R, et al.
miR-5195-3p Inhibits Proliferation and Invasion of Human Bladder Cancer Cells by Directly Targeting Oncogene KLF5.
Oncol Res. 2017; 25(7):1081-1087 [PubMed] Related Publications
miRNAs play a key role in the carcinogenesis of many cancers, including bladder cancer. In the current study, the role of miR-5195-3p, a quite recently discovered and poorly studied miRNA, in the proliferation and invasion of human bladder cancer cells was investigated. Our data displayed that, compared with healthy volunteers (control) and SU-HUC-1 normal human bladder epithelial cells, miR-5195-3p was sharply downregulated in bladder cancer patients and five human bladder cancer cell lines. The oligo miR-5195-3p mimic or miR-5195-3p antagomir was subsequently transfected into both T24 and BIU-87 bladder cancer cell lines. The miR-5195-3p mimic robustly increased the miR-5195-3p expression level and distinctly reduced the proliferation and invasion of T24 and BIU-87 cells. In contrast, the miR-5195-3p antagomir had an opposite effect on miR-5195-3p expression, cell proliferation, and invasion. Our data from bioinformatic and luciferase reporter gene assays identified that miR-5195-3p targeted the mRNA 3'-UTR of Krüppel-like factor 5 (KLF5), which is a proven proto-oncogene in bladder cancer. miR-5195-3p sharply reduced KLF5 expression and suppressed the expression or activation of its several downstream genes that are kinases improving cell survival or promoting cell cycle regulators, including ERK1/2, VEGFA, and cyclin D1. In conclusion, miR-5195-3p suppressed proliferation and invasion of human bladder cancer cells via suppression of KLF5.

Mihara N, Chiba T, Yamaguchi K, et al.
Minimal essential region for krüppel-like factor 5 expression and the regulation by specificity protein 3-GC box binding.
Gene. 2017; 601:36-43 [PubMed] Related Publications
Krüppel-like factor 5 (KLF5) transcriptionally controls the proliferation-differentiation balance of epithelium and is overexpressed in carcinomas. Although genomic region modifying KLF5 expression is widespread in different types of cells, the region that commonly regulates basal expression of the genes across cell-types is uncertain. In this study we determined the minimal essential region for the expression and its regulatory transcription factors using oral carcinoma cells. A reporter assay defined a 186bp region downstream of the transcription start site and a cluster of six GC boxes (GC1-GC6) as the minimal essential region. Mutation in the GC1 or GC6 regions but not other GC boxes significantly decreased the reporter expression. The decrease by the GC1 mutation was reproduced in the 2kbp full-length promoter, but not by the GC6 mutation. Additionally, specificity proteins (Sp) that can be expressed in epithelial cells and bind GC box, Sp3 co-localized with KLF5 in oral epithelium and carcinomas and chromatin immunoprecipitation analyses showed Sp3 as the prime GC1-binding protein. Inhibition of Sp-GC box binding by mithramycin A and knockdown of Sp3 by the short interfering RNA decreased expression of the reporter gene and endogenous KLF5. These data demonstrate that a 186bp region is the minimal essential region and that Sp3-GC1 binding is essential to the basal expression of KLF5.

Yuan W, Liu B, Wang X, et al.
CMTM3 decreases EGFR expression and EGF-mediated tumorigenicity by promoting Rab5 activity in gastric cancer.
Cancer Lett. 2017; 386:77-86 [PubMed] Related Publications
CMTM3 (CKLF-like MARVEL transmembrane domain containing 3), a tumor suppressor gene, is involved in multiple types of malignancies. CMTM3 knockdown promotes metastasis of gastric cancer via the STAT3/Twist1/EMT signaling pathway. Strong epidermal growth factor receptor1 (EGFR) expression is significantly associated with tumor metastasis and poor outcomes of gastric cancer patients. In this paper, we show that CMTM3 suppresses epidermal growth factor (EGF)-mediated migration and STAT3 signaling, downregulates EGFR expression via accelerating EGFR degradation in gastric cancer cells. CMTM3 colocalizes with early endosome markers Rab5 and EEA1. Co-immunoprecipitation (Co-IP) assay further confirms that CMTM3 interacts with Rab5. More importantly, CMTM3 markedly increases Rab5 activity. The suppressive effects of CMTM3 on EGFR expression and EGF-mediated migration can be abrogated by the siRNA against Rab5. Finally, we found that the C-terminal region of CMTM3 plays more important roles in the tumor suppressive effects of CMTM3. Overall, this study demonstrates that CMTM3 decreases EGFR expression, facilitates EGFR degradation, and inhibits the EGF-mediated tumorigenicity of gastric cancer cells via enhancing Rab5 activity.

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