KLF4

Gene Summary

Gene:KLF4; Kruppel like factor 4
Aliases: EZF, GKLF
Location:9q31.2
Summary:This gene encodes a protein that belongs to the Kruppel family of transcription factors. The encoded zinc finger protein is required for normal development of the barrier function of skin. The encoded protein is thought to control the G1-to-S transition of the cell cycle following DNA damage by mediating the tumor suppressor gene p53. Mice lacking this gene have a normal appearance but lose weight rapidly, and die shortly after birth due to fluid evaporation resulting from compromised epidermal barrier function. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2015]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:Krueppel-like factor 4
Source:NCBIAccessed: 15 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: KLF4 (cancer-related)

Xiu DH, Chen Y, Liu L, et al.
Tumor-suppressive role of Kruppel-like factor 4 (KLF-4) in colorectal cancer.
Genet Mol Res. 2017; 16(1) [PubMed] Related Publications
Kruppel-like factors (KLFs) are a group of transcriptional regulators that have recently been identified to exhibit tumor-suppressive function against various gastrointestinal cancers. The present study aims to investigate the expression patterns and prognostic value of KLF-4 in colorectal cancers (CRCs). KLF-4 levels in CRC tissues were examined via immunohistochemistry analysis, real-time quantitative polymerase chain reaction, and western blotting. The chi-square test was performed to evaluate the correlation between KLF-4 expression and the clinicopathological characteristics. Kaplan-Meier analysis was performed to assess the prognostic value of KLF-4 in CRC patients. In addition, we evaluated the effect of KLF-4 knockdown on the proliferation of CRC HT-29 cells. Our results showed significant downregulation of KLF-4 in 31 CRC samples, collected from CRC patients showing more malignant characteristics such as lymphatic metastasis, low tumor cell differentiation, and tumor recurrence. CRC patients in the low KLF-4 group were found to have reduced overall survival and decreased disease-free survival time. Moreover, HT-29 cells transfected with siRNA-KLF-4 showed increased proliferation compared to those transfected with control siRNA. In summary, lower KLF-4 expression was correlated with malignant CRC status and poor prognosis in CRC patients. Moreover, KLF-4 suppression promoted the proliferation of CRC cells in vitro. These results provide novel insights into the tumor suppressive role of KLF-4 in CRC.

Tian C, Yao S, Liu L, et al.
Klf4 inhibits tumor growth and metastasis by targeting microRNA-31 in human hepatocellular carcinoma.
Int J Mol Med. 2017; 39(1):47-56 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs or miRs) are short, endogenous non-coding RNA molecules, demonstrating abnormal expression in cancer initiation and progression. In this study, we profiled 18 differentially regulated miRNAs, including miRNA‑31, using miRNA array. Kruppel (or Krüppel)-like factor 4 (Klf4) is a transcription factor and putative tumor suppressor. Both were found to be significantly downregulated in liver cancer tissues and cells. However, little is known about the correlation between Klf4 and miRNA‑31 in hepatocellular carcinoma (HCC). The mRNA expression of Klf4 was decreased and inversely associated with the clinical stage, T classification and hepatitis B in patients with HCC, while the expression of miR‑31 was lower (r=0.326, P=0.018). Using cell counting kit 8 (CCK8) and Transwell migration assays, we found that Klf4 and miR‑31 inhibited the proliferation and metastasis of liver cancer cells. Moreover, we demonstrated that Klf4 directly binds to the promoter of miR‑31 and activates its transcription. In vitro experiments confirmed that Klf4 regulated miR‑31 and thereby inhibited HCC cell growth and metastasis. Taken together, our findings indicate that Klf4 directly regulates miR‑31 in HCC. Thus, miR-31 may serve as a potential diagnostic marker and therapeutic target in HCC.

Zhang Y, Huang Y, Jin Z, et al.
A convenient and effective strategy for the enrichment of tumor-initiating cell properties in prostate cancer cells.
Tumour Biol. 2016; 37(9):11973-11981 [PubMed] Related Publications
Stem-like prostate cancer (PrCa) cells, also called PrCa stem cells (PrCSCs) or PrCa tumor-initiating cells (PrTICs), are considered to be involved in the mediation of tumor metastasis and may be responsible for the poor prognosis of PrCa patients. Currently, the methods for PrTIC sorting are mainly based on cell surface marker or side population (SP). However, the rarity of these sorted cells limits the investigation of the molecular mechanisms and therapeutic strategies targeting PrTICs. For PrTIC enrichment, we induced cancer stem cell (CSC) properties in PrCa cells by transducing three defined factors (OCT3/4, SOX2, and KLF4), followed by culture with conventional serum-containing medium. The CSC properties in the transduced cells were evaluated by proliferation, cell cycle, SP assay, drug sensitivity technology, in vivo tumorigenicity, and molecular marker analysis of PrCSCs compared with parental cells and spheroids. After culture with serum-containing medium for 8 days, the PrCa cells transduced with the three factors showed significantly enhanced CSC properties in terms of marker gene expression, sphere formation, chemoresistance to docetaxel, and tumorigenicity. The percentage of CD133(+)/CD44(+) cells was ninefold higher in the transduced cell population than in the adherent PC3 cell population (2.25 ± 0.62 vs. 0.25 ± 0.12 %, respectively), and the SP increased to 1.22 ± 0.18 % in the transduced cell population, but was undetectable in the adherent population. This method can be used to obtain abundant PrTIC material and enables a complete understanding of PrTIC biology and development of novel therapeutic agents targeting PrTICs.

Roudi R, Madjd Z, Ebrahimi M, et al.
Evidence for embryonic stem-like signature and epithelial-mesenchymal transition features in the spheroid cells derived from lung adenocarcinoma.
Tumour Biol. 2016; 37(9):11843-11859 [PubMed] Related Publications
Identification of the cellular and molecular aspects of lung cancer stem cells (LCSCs) that are suggested to be the main culprit of tumor initiation, maintenance, drug resistance, and relapse is a prerequisite for targeted therapy of lung cancer. In the current study, LCSCs subpopulation of A549 cells was enriched, and after characterization of the spheroid cells, complementary DNA (cDNA) microarray analysis was applied to identify differentially expressed genes (DEGs) between the spheroid and parental cells. Microarray results were validated using quantitative real-time reverse transcription-PCR (qRT-PCR), flow cytometry, and western blotting. Our results showed that spheroid cells had higher clonogenic potential, up-regulation of stemness gene Sox2, loss of CD44 expression, and gain of CD24 expression compared to parental cells. Among a total of 160 genes that were differentially expressed between the spheroid cells and the parental cells, 104 genes were up-regulated and 56 genes were down-regulated. Analysis of cDNA microarray revealed an embryonic stem cell-like signature and over-expression of epithelial-mesenchymal transition (EMT)-associated genes in the spheroid cells. cDNA microarray results were validated at the gene expression level using qRT-PCR, and further validation was performed at the protein level by flow cytometry and western blotting. The embryonic stem cell-like signature in the spheroid cells supports two important notions: maintenance of CSCs phenotype by dedifferentiating mechanisms activated through oncogenic pathways and the origination of CSCs from embryonic stem cells (ESCs). PI3/AKT3, as the most common up-regulated pathway, and other pathways related to aggressive tumor behavior and EMT process can confer to the spheroid cells' high potential for metastasis and distant seeding.

Wang J, Wang B, Chen LQ, et al.
miR-10b promotes invasion by targeting KLF4 in osteosarcoma cells.
Biomed Pharmacother. 2016; 84:947-953 [PubMed] Related Publications
OBJECTIVE: Osteosarcoma is a common malignancy with high rate of metastasis. miR-10b has been reported to be expressed in many types of tumors abnormally and be associated with cancer carcinogenesis and progression. But the function of miR-10b in osteosarcoma is still unknown. So this study was aimed to investigate the role of miR-10b in osteosarcoma development.
METHODS: miR-10b expression in osteosarcoma tissues and osteosarcoma cells were detected using real time PCR. The effects of miR-10b on osteosarcoma cells proliferation, apoptosis, migration and invasion were detected using CCK-8 assay, flow cytometry, wound-healing assay and transwell assay, respectively. The relationship between miR-10b and KLF4 was evaluated using dual-luciferase assay, correlation analysis.
RESULTS: miR-10b was highly expressed in osteosarcoma tissues and osteosarcoma cells. Furthermore, inhibition of miR-10b in osteosarcoma cells depressed the cells proliferation, migration and invasion but promoted cells apoptosis. In addition, KLF4 was down-regulated by miR-10b and miR-10b expression was negatively related to KLF4 expression in osteosarcoma tissue, miR-10b participated in the process of osteosarcoma cells invasion by regulating KLF4 expression.
CONCLUSION: miR-10b is overexpressed in osteosarcoma and KLF4 is the direct target gene of miR-10b. Furthermore, miR-10b promotes osteosarcoma cells progression by downregulating KLF4 expression. These results suggest that miR-10b functions as an oncomiR and play an important role in osteosarcoma cellular processes at least partially through regulating KLF4; miR-10b may be a therapeutic target for osteosarcoma treatment.

Yuzawa S, Nishihara H, Tanaka S
Genetic landscape of meningioma.
Brain Tumor Pathol. 2016; 33(4):237-247 [PubMed] Related Publications
Meningioma is the most common intracranial tumor, arising from arachnoid cells of the meninges. Monosomy 22 and inactivating mutations of NF2 are well-known genetic alterations of meningiomas. More recently, mutations in TRAF7, AKT1, KLF4, SMO, and PIK3CA were identified by next-generation sequencing. We here reviewed 553 meningiomas for the mutational patterns of the six genes. NF2 aberration was observed in 55 % of meningiomas. Mutations of TRAF7, AKT1, KLF4, PIK3CA, and SMO were identified in 20, 9, 9, 4.5, and 3 % of cases, respectively. Altogether, 80 % of cases harbored at least one of the genetic alterations in these genes. NF2 alterations and mutations of the other genes were mutually exclusive with a few exceptions. Clinicopathologically, tumors with mutations in TRAF7/AKT1 and SMO shared specific features: they were located in the anterior fossa, median middle fossa, or anterior calvarium, and most of them were meningothelial or transitional meningiomas. TRAF7/KLF4 type meningiomas showed different characteristics in that they occurred in the lateral middle fossa and median posterior fossa as well as anterior fossa and median middle fossa, and contained a secretory meningioma component. We also discuss the mutational hotspots of these genes and other genetic/cytogenetic alterations contributing to tumorigenesis or progression of meningiomas.

Sharma S, Garg A, Dhanda RS, Kaul D
APOBEC3G governs the generation of truncated AATF protein to ensure oncogenic transformation.
Cell Biol Int. 2016; 40(12):1366-1371 [PubMed] Related Publications
The oncogenic potential of Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) was recently appreciated by the finding that revealed its ability to downregulate Kruppel-like factor 4 (KLF4) gene translation through its affinity for 3'UTR of KLF4 mRNA. Keeping in view the fact that KLF4 is known to repress apoptosis antagonizing transcription factor (AATF) gene expression, the present study employed stem cells as archetype model to explore the effect of APOBEC3G over-expression upon AATF gene expression within these cells as well as on the genes involved in oncogenic transformation. Such a study revealed that APOBEC3G had the ability to bind AATF mRNA within its third exon to facilitate the generation of truncated 23 kDa AATF translation product which, in turn, had the inherent capacity to be the crucial mediator of APOBEC3G induced oncogenic transformation within such cells.

Tang H, Jin Y, Jin S, et al.
Arsenite inhibits the function of CD133(+) CD13(+) liver cancer stem cells by reducing PML and Oct4 protein expression.
Tumour Biol. 2016; 37(10):14103-14115 [PubMed] Related Publications
Cancer stem cells (CSCs) can form new tumors and contribute to post-operative recurrence and metastasis. We showed that CD133(+)CD13(+) hepatocytes isolated from HuH7 cells and primary HCC cells display biochemical and functional characteristics typical of CSCs, suggesting that CD133(+)CD13(+) hepatocytes in primary HCC tumors function as CSCs. We also found that arsenite treatment reduced the viability and stemness of CD133(+)CD13(+) hepatocytes, enhanced the sensitivity of HuH7 cells to pirarubicin, and reduced the tumorigenicity of CD133(+)CD13(+) hepatocytes xenografts in mice. The effects of sodium arsenite treatment in CD133(+)CD13(+) hepatocytes were mediated by the post-transcriptional suppression of PML expression and the inhibition of Oct4, Sox2, and Klf4 expression at the transcriptional level. Incomplete rescue of Oct4 expression in arsenic-treated cells ectopically expressing an siRNA-resistant PML transcript suggested that OCT4 regulation in liver CSCs involves other factors in addition to PML. Our findings provide evidence of a specific role for PML in regulating Oct4 levels in liver CSCs and highlight the clinical importance of arsenic for improving the efficacy of other chemotherapeutic agents and the prevention of post-operative HCC recurrence and metastasis.

Gui X, Meng Z, McConnell YJ, et al.
Differing expression profiles of Notch/enterocyte and Wnt/secretory lineage signallings are associated with morphological diversity of appendiceal tumours.
J Clin Pathol. 2017; 70(1):40-50 [PubMed] Related Publications
BACKGROUND: Tumours of appendix, including classic carcinoid tumour (CCT), goblet cell carcinoid (GCC), low-grade appendiceal mucinous neoplasm, high-grade appendiceal mucinous neoplasm/mucinous carcinoma (MCA) and non-mucinous adenocarcinoma (NMA), show different and sometimes mixed morphological features. It was hypothesised that these tumours originate from common tumour stem cell(s) with potential of various cell lineage differentiation. In normal intestinal epithelium, absorptive lineage (enterocytes) differentiation is driven by Notch-Hes1 pathway, while secretory lineage is driven by Wnt-Math1 pathway and further separated by different downstream signallings into three sublineages (Gfi1-Klf4/Elf3 for goblet cells, Gfi1-Sox9 for Paneth cells and Ngn3-Pdx1/Beta2/Pax4 for enteroendocrine cells).
METHODS: The expressions of various signalling proteins in different appendiceal tumours were detected by immunohistochemistry on tumour tissue microarray.
RESULTS: CCT showed reduced Hes1/Elf3 and Sox9/Klf4 coupled with elevated Math1, in keeping with endocrine phenotype. As compared with CCT, GCC showed higher Klf4 and similar Ngn3/Pax4, indicative of a shift of differentiation towards goblet cells as well as endocrine cells. GCC displayed a Notch signalling similar to adenocarcinoma. Mucinous tumours showed lower Elf3 than normal appendiceal epithelium and higher Math1/Gfi1/Klf4, suggestive of a differentiation towards less enterocytes but more goblet cells. NMA showed Notch signalling similar to other glandular tumours, but lower Klf4. However, some seemingly paradoxical changes were also observed, probably suggesting gene mutations and/or our incomplete understanding of the intestinal cell differentiation.
CONCLUSIONS: Wnt/secretory lineage protein and Notch/absorptive lineage protein expression profiles are generally associated with the tumour cell differentiation and morphological diversity of common appendiceal tumours.

Liu Y, Lu R, Gu J, et al.
Aldehyde dehydrogenase 1A1 up-regulates stem cell markers in benzo[a]pyrene-induced malignant transformation of BEAS-2B cells.
Environ Toxicol Pharmacol. 2016; 45:241-50 [PubMed] Related Publications
Recently, Aldehyde dehydrogenase 1A1 (ALDH1A1) has been proposed to be a common marker of cancer stem cells and can be induced by benzo[a]pyrene (B[a]P) exposure. However, the underlying mechanism of how ALDH1A1 contributes to B[a]P-induced carcinogenesis in human bronchial epithelial cells remains unclear. Here, we found that B[a]P up-regulated expression levels of stem cell markers (ABCG2, SOX2, c-Myc and Klf4), epithelial-mesenchymal transition (EMT) associated genes (SNAIL1, ZEB1, TWIST and β-CATENIN) and cancer-related long non-coding RNAs (lncRNAs; HOTAIR and MALAT-1) in malignant B[a]P-transformed human bronchial epithelial cells (BEAS-2B-T cells), and these up-regulations were dependent on increased expression of ALDH1A1. The inhibition of endogenous ALDH1A1 expression down-regulated expression levels of stem cell markers and reversed the malignant phenotype as well as reduced the chemoresistance of BEAS-2B-T cells. In contrast, the overexpression of ALDH1A1 in BEAS-2B cells increased the expression of stem cell markers, facilitated cell transformation, promoted migratory ability and enhanced the drug resistance of BEAS-2B cells. Overall, our data indicates that ALDH1A1 promotes a stemness phenotype and plays a critical role in the BEAS-2B cell malignant transformation induced by B[a]P.

Nagata T, Shimada Y, Sekine S, et al.
KLF4 and NANOG are prognostic biomarkers for triple-negative breast cancer.
Breast Cancer. 2017; 24(2):326-335 [PubMed] Related Publications
BACKGROUND: Prognosis of breast cancer patients has been reported to depend on the expression of induced pluripotent stem (iPS) cell-inducing factors: KLF4 and NANOG. However, the relationship between KLF4 or NANOG expression in each breast cancer subtype and the life prognosis has not been elucidated.
METHOD: KLF4 and NANOG expression levels were evaluated in 208 patients using a newly developed tissue microarray (TMA). In vitro, siRNA against klf4 (siKLF4) was transfected in TNBC cell line MDA-MB-231, and the expression of KLF4 was inhibited.
RESULTS: Triple-negative breast cancer (TNBC) patients in KLF4 high-expression (upper) group had more favorable overall survival (OS) and disease-free survival (DFS) rates than KLF4 lower group (p = 0.0453 and p = 0.0427). In contrast, patients in the NANOG upper group had significantly poorer prognosis than lower group in TNBC breast cancer subtypes (p < 0.0001). Multivariate analysis showed that KLF4 (p = 0.0313), NANOG (p = 0.0002), and TNM stage (p = 0.0001) are mutually independent prognostic factors. It was also shown that the proliferation and invasion ability of siKLF4-induced TNBC cells were up-regulated significantly.
CONCLUSION: Our findings suggested that KLF4 and NANOG expression levels were favorable prognostic factors for TNBC patients. KLF4 also had an ability to inhibit the proliferation and invasion of TNBC.

Guo Y, An R, Zhao R, et al.
miR-375 exhibits a more effective tumor-suppressor function in laryngeal squamous carcinoma cells by regulating KLF4 expression compared with simple co-transfection of miR-375 and miR-206.
Oncol Rep. 2016; 36(2):952-60 [PubMed] Related Publications
MicroRNAs (miRNAs) are reported to be important regulators of cancer-related processes, and function either as oncogenes or as tumor-suppressor genes. It was found that miR-375 was downregulated in samples of laryngeal squamous cell carcinomas (LSCCs) as compared to the level noted in adjacent non-tumor tissues, and it was inversely correlated with T grade, lymph node metastases and clinical tumor stage. Overexpression of miR-375 led to a decreased protein level of Krüppel-like factor 4 (KLF4) and marked suppression of the proliferation and invasion, and induced apoptosis of LSCC cell line Hep-2 using Cell Counting Kit-8, Transwell chamber and cell cycle assays. In addition, we examined the influence of the upregulation of miR-206 alone and upregulation of both miR-375 and miR-206 on the expression of KLF4 and Hep-2 cell behavior. The results showed that compared with the function of miR-375 in tumor suppression by regulating KLF4, co-transfection of miR-375 and miR-206 exhibited a less effective inhibitory effect not only on tumor cell proliferation and invasion, but also on tumor cell apoptosis. Taken together, miR-375 is possibly a tumor suppressor in LSCC by regulating KLF4. In addition, simple overexpression of several miRNAs did not entail higher efficacy than a single miRNA, similar to co-transfecions of miR-375 and miR-206.

De Blasio A, Di Fiore R, Morreale M, et al.
Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231.
Int J Oncol. 2016; 48(6):2339-48 [PubMed] Related Publications
Triple-negative breast cancer (TNBC) is a clinically aggressive form of breast cancer that is unresponsive to endocrine agents or trastuzumab. TNBC accounts for ~10-20% of all breast cancer cases and represents the form with the poorest prognosis. Patients with TNBC are at higher risk of early recurrence, mainly in the lungs, brain and soft tissue, therefore, there is an urgent need for new therapies. The present study was carried out in MDA-MB-231 cells, where we assessed the role of caspase-8 (casp-8), a critical effector of death receptors, also involved in non‑apoptotic functions. Analysis of casp-8 mRNA and protein levels indicated that they were up-regulated with respect to the normal human mammalian epithelial cells. We demonstrated that silencing of casp-8 by small interfering-RNA, strongly decreased MDA-MB-231 cell growth by delaying G0/G1- to S-phase transition and increasing p21, p27 and hypo-phosphorylated/active form of pRb levels. Surprisingly, casp-8-knockdown, also potently increased both the migratory and metastatic capacity of MDA-MB‑231 cells, as shown by both wound healing and Matrigel assay, and by the expression of a number of related-genes and/or proteins such as VEGFA, C-MYC, CTNNB1, HMGA2, CXCR4, KLF4, VERSICAN V1 and MMP2. Among these, KLF4, a transcriptional factor with a dual role (activator and repressor), seemed to play critical roles. We suggest that in MDA-MB‑231 cells, the endogenous expression of casp-8 might keep the cells perpetually cycling through downregulation of KLF4, the subsequent lowering of p21 and p27, and the inactivation by hyperphosphorylation of pRb. Simultaneously, by lowering the expression of some migratory and invasive genes, casp-8 might restrain the metastatic ability of the cells. Overall, our findings showed that, in MDA-MB-231 cells, casp-8 might play some unusual roles which should be better explored, in order to understand whether it might be identified as a molecular therapeutic target.

Zhou Z, Tang AT, Wong WY, et al.
Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling.
Nature. 2016; 532(7597):122-6 [PubMed] Free Access to Full Article Related Publications
Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals. CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/β-catenin) and processes such as endothelial-mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development. Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.

Wei D, Wang L, Yan Y, et al.
KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis.
Cancer Cell. 2016; 29(3):324-38 [PubMed] Free Access to Full Article Related Publications
Understanding the molecular mechanisms of tumor initiation has significant impact on early cancer detection and intervention. To define the role of KLF4 in pancreatic ductal adenocarcinoma (PDA) initiation, we used molecular biological analyses and mouse models of klf4 gain- and loss-of-function and mutant Kras. KLF4 is upregulated in and required for acinar-to-ductal metaplasia. Klf4 ablation drastically attenuates the formation of pancreatic intraepithelial neoplasia induced by mutant Kras(G12D), whereas upregulation of KLF4 does the opposite. Mutant KRAS and cellular injuries induce KLF4 expression, and ectopic expression of KLF4 in acinar cells reduces acinar lineage- and induces ductal lineage-related marker expression. These results demonstrate that KLF4 induces ductal identity in PanIN initiation and may be a potential target for prevention of PDA initiation.

Mori E, Fujikura J, Noguchi M, et al.
Impaired adipogenic capacity in induced pluripotent stem cells from lipodystrophic patients with BSCL2 mutations.
Metabolism. 2016; 65(4):543-56 [PubMed] Related Publications
OBJECTIVE: Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by marked scarcity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early-onset diabetes. Mutation of the BSCL2/SEIPIN gene causes the most severe form of CGL. The aim of this study was to generate induced pluripotent stem (iPS) cells from patients with CGL harboring BSCL2/SEIPIN mutations.
METHODS: Skin biopsies were obtained from two Japanese patients with CGL harboring different nonsense mutations (E189X and R275X) in BSCL2/SEIPIN. The fibroblasts thus obtained were infected with retroviruses encoding OCT4, SOX2, c-MYC, and KLF4. The generated iPS cells were evaluated for pluripotency by examining the expression of pluripotency markers (alkaline phosphatase, SSEA-4, TRA-1-60, and NANOG) and their ability to differentiate to three germ layers in vitro by forming embryoid bodies, and to form teratomas in vivo. Adipogenic capacity of differentiated BSCL2-iPS cells was determined by oil red O and adipose differentiation-related protein (ADRP) staining. Rescue experiments were also performed using stable expression of wild-type BSCL2. A coimmunoprecipitation assay was conducted to investigate the interaction of SEIPIN with ADRP.
RESULTS: iPS cells were generated from fibroblasts of the two patients with CGL. Each of the patient-derived iPS (BSCL2-iPS) clones showed all of the hallmarks of pluripotency and could differentiate into derivatives of all three germ layers in vitro by forming embryoid bodies, and form teratomas after injection into mouse testes. BSCL2-iPS cells maintained the mutations in BSCL2 and lacked intact BSCL2. Upon adipogenic differentiation, BSCL2-iPS cells exhibited marked reduction of lipid droplet formation concomitant with diffuse cytoplasmic distribution of ADRP, compared with iPS cells from healthy individuals. Forced expression of BSCL2 not only rescued the lipid accumulation defects, but also restored cytoplasmic punctate localization of ADRP in BSCL2-iPS cells. Coimmunoprecipitation indicated SEIPIN interacted with ADRP.
CONCLUSION: BSCL2-iPS cells that recapitulate the lipodystrophic phenotypes in vitro could provide valuable models with which to study the physiology of lipid accumulation and the pathology of human lipodystrophy. We found that BSCL2 defines the localization of ADRP, which has a role in lipid accumulation and adipogenic differentiation.

Müller M, Hermann PC, Liebau S, et al.
The role of pluripotency factors to drive stemness in gastrointestinal cancer.
Stem Cell Res. 2016; 16(2):349-57 [PubMed] Related Publications
A better molecular understanding of gastrointestinal cancers arising either from the stomach, the pancreas, the intestine, or the liver has led to the identification of a variety of potential new molecular therapeutic targets. However, in most cases surgery remains the only curative option. The intratumoral cellular heterogeneity of cancer stem cells, bulk tumor cells, and stromal cells further limits straightforward targeting approaches. Accumulating evidence reveals an intimate link between embryonic development, stem cells, and cancer formation. In line, a growing number of oncofetal proteins are found to play common roles within these processes. Cancer stem cells share features with true stem cells by having the capacity to self-renew in a de-differentiated state, to generate heterogeneous types of differentiated progeny, and to give rise to the bulk tumor. Further, various studies identified genes in cancer stem cells, which were previously shown to regulate the pluripotency circuitry, particularly the so-called "Yamanaka-Factors" (OCT4, KLF4, SOX2, and c-MYC). However, the true stemness potential of cancer stem cells and the role and expression pattern of such pluripotency genes in various tumor cell types remain to be explored. Here, we summarize recent findings and discuss the potential mechanisms involved, and link them to clinical significance with a particular focus on gastrointestinal cancers.

Vidal AF, Cruz AM, Magalhães L, et al.
hsa-miR-29c and hsa-miR-135b differential expression as potential biomarker of gastric carcinogenesis.
World J Gastroenterol. 2016; 22(6):2060-70 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate the expression profiles of hsa-miR-29c and hsa-miR-135b in gastric mucosal samples and their values as gastric carcinogenesis biomarkers.
METHODS: The expression levels of hsa-miR-29c and hsa-miR-135b in normal gastric mucosa, non-atrophic chronic gastritis, intestinal metaplasia and intestinal-type gastric adenocarcinoma were analysed using quantitative real-time PCR. The difference between hsa-miR-29c and hsa-miR-135b expression profiles in the grouped samples was evaluated by ANOVA and Student's t-test tests. The results were adjusted for multiple testing by using Bonferroni's correction. P values ≤ 0.05 were considered statistically significant. To evaluate hsa-miR-29c and hsa-miR-135b expressions as potential biomarkers of gastric carcinogenesis, we performed a receiver operating characteristic curve analysis and the derived area under the curve, and a Categorical Principal Components Analysis. In silico identification of the genetic targets of hsa-miR-29c and hsa-miR-135b was performed using different prediction tools, in order to identify possible genes involved in gastric carcinogenesis.
RESULTS: The expression levels of hsa-miR-29c were higher in normal gastric mucosal samples, and decreased progressively in non-atrophic chronic gastritis samples, intestinal metaplasia samples and intestinal-type gastric adenocarcinoma samples. The expression of hsa-miR-29c in the gastric lesions showed that non-atrophic gastritis have an intermediate profile to gastric normal mucosa and intestinal-type gastric adenocarcinoma, and that intestinal metaplasia samples presented an expression pattern similar to that in intestinal-type gastric adenocarcinoma. This microRNA (miRNA) has a good discriminatory accuracy between normal gastric samples and (1) intestinal-type gastric adenocarcinoma; and (2) intestinal metaplasia, and regulates the DMNT3A oncogene. hsa-miR-135b is up-regulated in non-atrophic chronic gastritis and intestinal metaplasia samples and down-regulated in normal gastric mucosa and intestinal-type gastric adenocarcinoma samples. Non-atrophic chronic gastritis and intestinal metaplasia are significantly different from normal gastric mucosa samples. hsa-miR-135b expression presented a greater discriminatory accuracy between normal samples and gastric lesions. This miRNA was associated with Helicobacter pylori presence in non-atrophic chronic gastritis samples and regulates the APC and KLF4 tumour suppressor genes.
CONCLUSION: Our results provide evidence of epigenetic alterations in non-atrophic chronic gastritis and intestinal metaplasia and suggest that hsa-miR-29c and hsa-miR-135b are promising biomarkers of gastric carcinogenesis.

Pelossof R, Chow OS, Fairchild L, et al.
Integrated genomic profiling identifies microRNA-92a regulation of IQGAP2 in locally advanced rectal cancer.
Genes Chromosomes Cancer. 2016; 55(4):311-21 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Locally advanced rectal cancer (LARC) is treated with chemoradiation prior to surgical excision, leaving residual tumors altered or completely absent. Integrating layers of genomic profiling might identify regulatory pathways relevant to rectal tumorigenesis and inform therapeutic decisions and further research. We utilized formalin-fixed, paraffin-embedded pre-treatment LARC biopsies (n=138) and compared copy number, mRNA, and miRNA expression with matched normal rectal mucosa. An integrative model was used to predict regulatory interactions to explain gene expression changes. These predictions were evaluated in vitro using multiple colorectal cancer cell lines. The Cancer Genome Atlas (TCGA) was also used as an external cohort to validate our genomic profiling and predictions. We found differentially expressed mRNAs and miRNAs that characterize LARC. Our integrative model predicted the upregulation of miR-92a, miR-182, and miR-221 expression to be associated with downregulation of their target genes after adjusting for the effect of copy number alterations. Cell line studies using miR-92a mimics and inhibitors demonstrate that miR-92a expression regulates IQGAP2 expression. We show that endogenous miR-92a expression is inversely associated with endogenous KLF4 expression in multiple cell lines, and that this relationship is also present in rectal cancers of TCGA. Our integrative model predicted regulators of gene expression change in LARC using pre-treatment FFPE tissues. Our methodology implicated multiple regulatory interactions, some of which are corroborated by independent lines of study, while others indicate new opportunities for investigation.

Kaur S, Elkahloun AG, Singh SP, et al.
A function-blocking CD47 antibody suppresses stem cell and EGF signaling in triple-negative breast cancer.
Oncotarget. 2016; 7(9):10133-52 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
CD47 is a signaling receptor for thrombospondin-1 and the counter-receptor for signal-regulatory protein-α (SIRPα). By inducing inhibitory SIRPα signaling, elevated CD47 expression by some cancers prevents macrophage phagocytosis. The anti-human CD47 antibody B6H12 inhibits tumor growth in several xenograft models, presumably by preventing SIRPα engagement. However, CD47 signaling in nontransformed and some malignant cells regulates self-renewal, suggesting that CD47 antibodies may therapeutically target cancer stem cells (CSCs). Treatment of MDA-MB-231 breast CSCs with B6H12 decreased proliferation and asymmetric cell division. Similar effects were observed in T47D CSCs but not in MCF7 breast carcinoma or MCF10A breast epithelial cells. Gene expression analysis in breast CSCs treated with B6H12 showed decreased expression of epidermal growth factor receptor (EGFR) and the stem cell transcription factor KLF4. EGFR and KLF4 mRNAs are known targets of microRNA-7, and B6H12 treatment correspondingly enhanced microRNA-7 expression in breast CSCs. B6H12 treatment also acutely inhibited EGF-induced EGFR tyrosine phosphorylation. Expression of B6H12-responsive genes correlated with CD47 mRNA expression in human breast cancers, suggesting that the CD47 signaling pathways identified in breast CSCs are functional in vivo. These data reveal a novel SIRPα-independent mechanism by which therapeutic CD47 antibodies could control tumor growth by autonomously forcing differentiation of CSC.

Ghaleb AM, Elkarim EA, Bialkowska AB, Yang VW
KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis.
Mol Cancer Res. 2016; 14(4):385-96 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
UNLABELLED: The zinc finger transcription factor Krüppel-like factor 4 (KLF4) is frequently downregulated in colorectal cancer. Previous studies showed that KLF4 is a tumor suppressor in the intestinal tract and plays an important role in DNA damage-repair mechanisms. Here, the in vivo effects of Klf4 deletion were examined from the mouse intestinal epithelium (Klf4(ΔIS)) in a genetic or pharmacological setting of colonic tumorigenesis:Apc(Min/⁺) mutation or carcinogen treatment with azoxymethane (AOM), respectively.Klf4 (ΔIS)/Apc (Min/⁺) mice developed significantly more colonic adenomas with 100% penetrance as compared with Apc(Min/⁺) mice with intact Klf4 (Klf4(fl/fl)/Apc (Min/⁺)). The colonic epithelium of Klf4 (ΔIS)/Apc (Min/⁺)mice showed increased mTOR pathway activity, together with dysregulated epigenetic mechanism as indicated by altered expression of HDAC1 and p300. Colonic adenomas from both genotypes stained positive for γH2AX, indicating DNA double-strand breaks. InKlf4 (ΔIS)/Apc (Min/+) mice, this was associated with reduced nonhomologous end joining (NHEJ) repair and homologous recombination repair (HRR) mechanisms as indicated by reduced Ku70 and Rad51 staining, respectively. In a separate model, following treatment with AOM, Klf4 (ΔIS) mice developed significantly more colonic tumors than Klf4 (fl/fl) mice, with more Klf4 (ΔIS) mice harboring K-Rasmutations than Klf4 (fl/fl)mice. Compared with AOM-treated Klf4 (fl/fl)mice, adenomas of treated Klf4 (ΔIS) mice had suppressed NHEJ and HRR mechanisms, as indicated by reduced Ku70 and Rad51 staining. This study highlights the important role of KLF4 in suppressing the development of colonic neoplasia under different tumor-promoting conditions.
IMPLICATIONS: The study demonstrates that KLF4 plays a significant role in the pathogenesis of colorectal neoplasia.

Ashaie MA, Chowdhury EH
Cadherins: The Superfamily Critically Involved in Breast Cancer.
Curr Pharm Des. 2016; 22(5):616-38 [PubMed] Related Publications
Breast cancer, one of the leading causes of mortality and morbidity among females, is regulated in part by diverse classes of adhesion molecules one of which is known as cadherins. Located at adherens junctions, the members of this superfamily are responsible for upholding proper cell-cell adhesion. Cadherins possess diverse structures and functions and any alteration in their structures or functions causes impeding of normal mammary cells development and maintenance, thus leading to breast malignancy. E-, N-, P-, VE-, Proto-, desmosomal and FAT cadherins have been found to regulate breast cancer in positive as well as negative fashion, whereby both Ecadherin (CDH1) and N-cadherin (CDH2) contribute significantly towards transitioning from epithelial state to mesenchymal state (EMT) and enacting the abnormal cells to invade and metastasize nearby and distant tissues. Aberration in gene expression of cadherins can be either due to somatic or epigenetic silencing or via transcriptional factors. Besides other cadherins, E-cadherin which serves as hallmark of EMT is associated with several regulatory factors such as Snail, Slug, Twist, Zeb, KLF4, NFI, TBX2, SIX, b-Myb, COX-2, Arf6, FOXA2, GATA3 and SMAR1, which modulate E-cadherin gene transcription to promote or represses tumor invasion and colonization. Signaling molecules such as Notch, TGF-β, estrogen receptors, EGF and Wnt initiate numerous signaling cascades via these vital factors of cell programming, controlling expression of E-cadherin at transcriptional (mRNA) and protein level. Thus, interactions of cadherins with their roles in tumor suppression and oncogenic transformation can be beneficial in providing valuable insights for breast cancer diagnosis and therapeutics development.

Jia ZM, Ai X, Teng JF, et al.
p21 and CK2 interaction-mediated HDAC2 phosphorylation modulates KLF4 acetylation to regulate bladder cancer cell proliferation.
Tumour Biol. 2016; 37(6):8293-304 [PubMed] Related Publications
Krüppel-like factor 4 (KLF4) is a transcription factor involved in both tumor suppression and oncogenesis as a transcriptional activator or repressor in a context-dependent manner. KLF4 acts as a regulator of p53 depending on p21 status in breast cancer. However, the mechanisms underlying the distinct role of KLF4 remain poorly understood. Here, we revealed that p21 depletion converted KLF4 from a cell cycle inhibitor to a promoter of bladder cancer cell proliferation. Additionally, KLF4 was acetylated in a p21-dependent manner to inhibit bladder cancer cell growth as a tumor suppressor. However, deacetylated KLF4 functioned as an oncogene promoting bladder cancer cell proliferation. Mechanistically, p21 and CK2 interaction, but not CK2 alone, enhanced HDAC2 phosphorylation and restricted KLF4 deacetylation and subsequent tumor promotion. Furthermore, we observed that KLF4 was acetylated by CBP/p300 and that overexpression of CBP resulted in KLF4 acetylation and tumor suppression even in p21-depleted bladder cancer cells. Moreover, we discovered that Notch-1 knockdown-induced KLF4 is acetylated form of KLF4, which may mediate Notch-1 function in bladder cancer cell proliferation. Our data demonstrate that KLF4 acts as a tumor suppressor or oncogene to activate or repress target gene transcription depending on its acetylation status, which is regulated by p21 and CK2 interaction-mediated HDAC2 phosphorylation. Targeting KLF4 at the post-transcriptional levels may provide novel insight for bladder cancer therapy.

Huang J, Liu K, Song D, et al.
Krüppel-like factor 4 promotes high-mobility group box 1-induced chemotherapy resistance in osteosarcoma cells.
Cancer Sci. 2016; 107(3):242-9 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Osteosarcoma is the most common primary malignant bone tumor, and the frequent acquisition of chemoresistance is often an obstacle to achieving favorable outcomes during chemotherapy. Recently, Krüppel-like factor 4 (KLF4) has been shown to be associated with chemotherapy resistance in a few tumors; however, the involvement of KLF4 in chemotherapy resistance in osteosarcoma cells remains unknown. In this study, quantitative real-time PCR and western blot analysis revealed that KLF4 expression was significantly increased in response to cisplatin, methotrexate and doxorubicin treatment in osteosarcoma cells, and knockdown of KLF4 increased sensitivity to these anticancer drugs by decreasing cellular clonogenic ability and increasing apoptosis. Moreover, our data suggest that KLF4-regulated drug resistance might, at least partially, positively regulate high-mobility group box 1 (HMGB1), which was found to be a significant contributor to chemoresistance in osteosarcoma cells in our previous study. In summary, this study highlights the significance of KLF4/HMGB1 interaction in regulating chemotherapy resistance, and suggests that targeting KLF4/high-mobility group box 1 may be a therapeutic strategy for osteosarcoma chemotherapy.

Yu AQ, Ding Y, Li CL, et al.
TALEN-induced disruption of Nanog expression results in reduced proliferation, invasiveness and migration, increased chemosensitivity and reversal of EMT in HepG2 cells.
Oncol Rep. 2016; 35(3):1657-63 [PubMed] Related Publications
Accumulating evidence indicates that Nanog plays a central role in modulating the biological behaviors of human hepatocellular carcinoma (HCC). However, the underlying mechanisms remain unclear. In the present study, we employed transcription activator-like effector nucleases (TALEN) to disrupt Nanog expression in HepG2 cells and obtained subcloned cells with diallelic Nanog mutations. Significantly, we found that the expression of pluripotency factors Sox2, Oct4 and Klf4, as well as expression of cancer stem cell (CSC) marker CD133, in the Nanog-targeted HepG2 cells was markedly downregulated. This finding suggests that Nanog may play an important role in maintaining the pluripotency and malignancy of HepG2 cells. We also revealed that Nanog regulated cell proliferation by modulating the expression of cyclin D1/D3/E1 and CDK2, respectively. Additionally, the disruption of Nanog resulted in the downregulation of epithelial-mesenchymal transition (EMT) regulators Snail and Twist, which contributed to the elevated level of epithelial marker E-cadherin, and to the decreased level of mesenchymal markers N-cadherin and vimentin in the HepG2 cells. In addition, the Nanog-targeted HepG2 cells exhibited reduced ability of invasion, migration and chemoresistance in vitro. In conclusion, the disruption of Nanog expression results in less proliferation, invasiveness, migration, more chemosensitivity and reversal of EMT in HepG2 cells, by which Nanog plays crucial roles in influencing the malignant phenotype of HepG2 cells.

Schwickert A, Weghake E, Brüggemann K, et al.
microRNA miR-142-3p Inhibits Breast Cancer Cell Invasiveness by Synchronous Targeting of WASL, Integrin Alpha V, and Additional Cytoskeletal Elements.
PLoS One. 2015; 10(12):e0143993 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
MicroRNAs (miRNAs, micro ribonucleic acids) are pivotal post-transcriptional regulators of gene expression. These endogenous small non-coding RNAs play significant roles in tumorigenesis and tumor progression. miR-142-3p expression is dysregulated in several breast cancer subtypes. We aimed at investigating the role of miR-142-3p in breast cancer cell invasiveness. Supported by transcriptomic Affymetrix array analysis and confirmatory investigations at the mRNA and protein level, we demonstrate that overexpression of miR-142-3p in MDA-MB-231, MDA-MB-468 and MCF-7 breast cancer cells leads to downregulation of WASL (Wiskott-Aldrich syndrome-like, protein: N-WASP), Integrin-αV, RAC1, and CFL2, molecules implicated in cytoskeletal regulation and cell motility. ROCK2, IL6ST, KLF4, PGRMC2 and ADCY9 were identified as additional targets in a subset of cell lines. Decreased Matrigel invasiveness was associated with the miR-142-3p-induced expression changes. Confocal immunofluorescence microscopy, nanoscale atomic force microscopy and digital holographic microscopy revealed a change in cell morphology as well as a reduced cell volume and size. A more cortical actin distribution and a loss of membrane protrusions were observed in cells overexpressing miR-142-3p. Luciferase activation assays confirmed direct miR-142-3p-dependent regulation of the 3'-untranslated region of ITGAV and WASL. siRNA-mediated depletion of ITGAV and WASL resulted in a significant reduction of cellular invasiveness, highlighting the contribution of these factors to the miRNA-dependent invasion phenotype. While knockdown of WASL significantly reduced the number of membrane protrusions compared to controls, knockdown of ITGAV resulted in a decreased cell volume, indicating differential contributions of these factors to the miR-142-3p-induced phenotype. Our data identify WASL, ITGAV and several additional cytoskeleton-associated molecules as novel invasion-promoting targets of miR-142-3p in breast cancer.

Morris VA, Cummings CL, Korb B, et al.
Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets.
Mol Cell Biol. 2015; 36(4):559-73 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Acute myeloid leukemia (AML) is characterized by increased proliferation and blocked differentiation of hematopoietic progenitors mediated, in part, by altered myeloid transcription factor expression. Decreased Krüppel-like factor 4 (KLF4) expression has been observed in AML, but how decreased KLF4 contributes to AML pathogenesis is largely unknown. We demonstrate decreased KLF4 expression in AML patient samples with various cytogenetic aberrations, confirm that KLF4 overexpression promotes myeloid differentiation and inhibits cell proliferation in AML cell lines, and identify new targets of KLF4. We have demonstrated that microRNA 150 (miR-150) expression is decreased in AML and that reintroducing miR-150 expression induces myeloid differentiation and inhibits proliferation of AML cells. We show that KLF family DNA binding sites are necessary for miR-150 promoter activity and that KLF2 or KLF4 overexpression induces miR-150 expression. miR-150 silencing, alone or in combination with silencing of CDKN1A, a well-described KLF4 target, did not fully reverse KLF4-mediated effects. Gene expression profiling and validation identified putative KLF4-regulated genes, including decreased MYC and downstream MYC-regulated gene expression in KLF4-overexpressing cells. Our findings indicate that decreased KLF4 expression mediates antileukemic effects through regulation of gene and microRNA networks, containing miR-150, CDKN1A, and MYC, and provide mechanistic support for therapeutic strategies increasing KLF4 expression.

Cuttano R, Rudini N, Bravi L, et al.
KLF4 is a key determinant in the development and progression of cerebral cavernous malformations.
EMBO Mol Med. 2016; 8(1):6-24 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Cerebral cavernous malformations (CCMs) are vascular malformations located within the central nervous system often resulting in cerebral hemorrhage. Pharmacological treatment is needed, since current therapy is limited to neurosurgery. Familial CCM is caused by loss-of-function mutations in any of Ccm1, Ccm2, and Ccm3 genes. CCM cavernomas are lined by endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndMT). This switch in phenotype is due to the activation of the transforming growth factor beta/bone morphogenetic protein (TGFβ/BMP) signaling. However, the mechanism linking Ccm gene inactivation and TGFβ/BMP-dependent EndMT remains undefined. Here, we report that Ccm1 ablation leads to the activation of a MEKK3-MEK5-ERK5-MEF2 signaling axis that induces a strong increase in Kruppel-like factor 4 (KLF4) in ECs in vivo. KLF4 transcriptional activity is responsible for the EndMT occurring in CCM1-null ECs. KLF4 promotes TGFβ/BMP signaling through the production of BMP6. Importantly, in endothelial-specific Ccm1 and Klf4 double knockout mice, we observe a strong reduction in the development of CCM and mouse mortality. Our data unveil KLF4 as a therapeutic target for CCM.

Lim HJ, Kim J, Park CH, et al.
Regulation of c-Myc Expression by Ahnak Promotes Induced Pluripotent Stem Cell Generation.
J Biol Chem. 2016; 291(2):752-61 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
We have previously reported that Ahnak-mediated TGFβ signaling leads to down-regulation of c-Myc expression. Here, we show that inhibition of Ahnak can promote generation of induced pluripotent stem cells (iPSC) via up-regulation of endogenous c-Myc. Consistent with the c-Myc inhibitory role of Ahnak, mouse embryonic fibroblasts from Ahnak-deficient mouse (Ahnak(-/-) MEF) show an increased level of c-Myc expression compared with wild type MEF. Generation of iPSC with just three of the four Yamanaka factors, Oct4, Sox2, and Klf4 (hereafter 3F), was significantly enhanced in Ahnak(-/-) MEF. Similar results were obtained when Ahnak-specific shRNA was applied to wild type MEF. Of note, expressionof Ahnak was significantly induced during the formation of embryoid bodies from embryonic stem cells, suggesting that Ahnak-mediated c-Myc inhibition is involved in embryoid body formation and the initial differentiation of pluripotent stem cells. The iPSC from 3F-infected Ahnak(-/-) MEF cells (Ahnak(-/-)-iPSC-3F) showed expression of all stem cell markers examined and the capability to form three primary germ layers. Moreover, injection of Ahnak(-/-)-iPSC-3F into athymic nude mice led to development of teratoma containing tissues from all three primary germ layers, indicating that iPSC from Ahnak(-/-) MEF are bona fide pluripotent stem cells. Taken together, these data provide evidence for a new role for Ahnak in cell fate determination during development and suggest that manipulation of Ahnak and the associated signaling pathway may provide a means to regulate iPSC generation.

Sławek S, Szmyt K, Fularz M, et al.
Pluripotency transcription factors in lung cancer-a review.
Tumour Biol. 2016; 37(4):4241-9 [PubMed] Related Publications
Lung cancer is the leading cause of cancer-related mortality worldwide. Diagnosis of lung cancer in an early stage is still a challenge due to the asymptomatic course of early stages of the disease and the lack of a standard screening program for the population. Nowadays, learning about the mechanisms that lead to cancerogenesis in the lung is crucial for the development of new diagnostic and therapeutic strategies. Recently, many studies have proved that cancer stem cells (CSCs) are responsible for the initiation, progression, metastasis, recurrence, and even resistance of chemo- and radiotherapeutic treatment in patients with lung cancer. The expression of pluripotency transcription factors is responsible for stemness properties. In this review, we summarize the current knowledge on the role of CSCs and pluripotency transcription factors in lung carcinogenesis.

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