E-cadherin is a novel transcriptional target of the KLF6 tumor suppressor

DiFeo, Analisa; Narla, Goutham; Camacho-Vanegas, Olga; Nishio, Hisahide; Rose, Stephen L.; Buller, Richard E.; Friedman, Scott L.; Walsh, Martin J.; Martignetti, J.

doi:10.1038/sj.onc.1209611

Cited by 70 publications

(60 citation statements)

References 31 publications

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“…After cells were transfected with siE-cad or C-siRNA, they were plated at confluent density on the insert and maintained for an additional 48 h. Levels of paracellular permeability were measured 2 h after addition of [ increased c-Myc activates E-cadherin transcription through direct interaction with the E-Pal box. It has been recognized for many years that levels of the E-cadherin in various tissues are highly regulated and its expression is cell type dependent in manner (11,12,30,31,39). As shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Polyamines regulate E-cadherin transcription through c-Myc modulating intestinal epithelial barrier function

Liu

Guo²,

Rao³

et al. 2009

American Journal of Physiology-Cell Physiology

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The integrity of the intestinal epithelial barrier depends on intercellular junctions that are highly regulated by numerous extracellular and intracellular factors. E-cadherin is found primarily at the adherens junctions in the intestinal mucosa and mediates strong cell-cell contacts that have a functional role in forming and regulating the epithelial barrier. Polyamines are necessary for E-cadherin expression, but the exact mechanism underlying polyamines remains elusive. The current study was performed to determine whether polyamines induce E-cadherin expression through the transcription factor c-Myc and whether polyamine-regulated E-cadherin plays a role in maintenance of the epithelial barrier integrity. Decreasing cellular polyamines reduced c-Myc and repressed E-cadherin transcription as indicated by a decrease in levels of E-cadherin promoter activity and its mRNA. Forced expression of the c-myc gene by infection with adenoviral vector containing c-Myc cDNA stimulated E-cadherin promoter activity and increased Ecadherin mRNA and protein levels in polyamine-deficient cells. Experiments using different E-cadherin promoter mutants revealed that induction of E-cadherin transcription by c-Myc was mediated through the E-Pal box located at the proximal region of the E-cadherin promoter. Decreased levels of E-cadherin in polyamine-deficient cells marginally increased basal levels of paracellular permeability but, remarkably, potentiated H2O2-induced epithelial barrier dysfunction. E-cadherin silencing by transfection with its specific small interfering RNA also increased vulnerability of the epithelial barrier to H2O2. These results indicate that polyamines enhance E-cadherin transcription by activating c-Myc, thus promoting function of the epithelial barrier.

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Section: Discussionmentioning

confidence: 99%

Polyamines regulate E-cadherin transcription through c-Myc modulating intestinal epithelial barrier function

Liu

Guo²,

Rao³

et al. 2009

American Journal of Physiology-Cell Physiology

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“…In this system, ectopic expression of KLF6 in a range similar to that of normal cells leads to growth inhibition and enhanced differentiation, as reflected in decreased mRNA levels of cyclin D1 and beta catenin associated with induction of albumin, E-cadherin, and TTR mRNAs, with decreased AFP expression. It is uncertain if each of these genes represents a direct transcriptional target of KLF6, except for E-cadherin, which interacts directly with the KLF6 promoter [25].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of KLF6 is an early event in hepatocarcinogenesis, and stimulates proliferation while reducing differentiation

Kremer-Tal

Narla

Chen

et al. 2007

Journal of Hepatology

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Background/Aims-Hepatocellular carcinoma (HCC) has the most rapidly rising cancer incidence in the US and Europe. The KLF6 tumor suppressor is frequently inactivated in HCC by loss-of-heterozygosity (LOH) and/or mutation.Methods-Here we have analyzed 33 HBV-and 40 HCV-related HCCs for mRNA expression of wildtype KLF6 (wtKLF6) as well as the KLF6 variant 1 (SV1), a truncated, growth-promoting variant that antagonizes wtKLF6 function. The HCV-related tumors analyzed represented the full histologic spectrum from cirrhosis and dysplasia to metastatic cancer.Results-Expression of KLF6 mRNA is decreased in 73% of HBV-associated HCCs compared to matched surrounding tissue (ST), with reductions of ~80% in one-third of the patients. KLF6 mRNA expression is also reduced in dysplastic nodules from patients with HCV compared to cirrhotic livers (p < 0.005), with an additional, marked decrease in the very advanced, metastatic ). An increased ratio of KLF6SV1/wt KLF6 is present in a subset (6/33, 18%) of the HBV-related HCCs compared to matched ST. Reconstituting KLF6 in HepG2 cells by retroviral infection decreased proliferation and related markers including cyclin D1 and betacatenin, increased cellular differentiation based on induction of albumin, E-cadherin, and decreased alpha fetoprotein.Conclusions-We conclude that reduced KLF6 expression is common in both HBV-and HCVrelated HCCs and occurs at critical stages during cancer progression. Effects of KLF6 are attributable to regulation of genes controlling hepatocyte growth and differentiation.

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“…We decided to extend our observations to other neoplastic cell lines that, different from MDA-MB-435, are of epithelial origin, express the junctional adhesion molecule E-cadherin and grow as compact aggregates with well-defined intercellular contacts (Nishimura et al, 2003;DiFeo et al, 2006). Specifically, we examined Skov-3 (ovarian carcinoma) and Hec-1A (endometrial carcinoma).…”

Section: Effects Of the Modulation Of The Slit/robo Pathway On Hgf-dementioning

confidence: 99%

The Slit/Robo System Suppresses Hepatocyte Growth Factor-dependent Invasion and Morphogenesis

Stella

Trusolino

Comoglio

2009

MBoC

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The Slit protein acts through the Roundabout receptor as a paracrine chemorepellent in axon guidance and as an inhibitor in leukocyte chemotaxis, but its role in epithelial cell motility and morphogenesis remains largely unexplored. We report that nontransformed epithelial cells and cancerous cells empower the Slit-2/Robo1 signaling system to limit outward migration in response to motogenic attractants and to remain positionally confined within their primitive location. Short hairpin RNA-mediated depletion of SLIT-2 or ectopic expression of a soluble decoy Robo enhance hepatocyte growth factor (HGF)-induced migration, matrix invasion, and tubulogenesis, concomitantly with the up-regulation of Cdc-42 and the down-modulation of Rac-1 activities. Accordingly, autocrine overexpression or exogenous administration of Slit-2 prevent HGF-triggered motile responses, reduce Cdc-42 activation, and stimulate Rac-1. This antimigratory activity of Slit-2 derives from the inhibition of actin-based protrusive forces and from an increased adhesive strength of cadherinmediated intercellular contacts. These results disclose a novel function for Slit and Robo in the inhibition of growth factor-mediated epithelial cell motility and morphogenesis, invoking a critical role for both molecules as natural antagonists of neoplastic invasive growth.

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E-cadherin is a novel transcriptional target of the KLF6 tumor suppressor

Cited by 70 publications

References 31 publications

Polyamines regulate E-cadherin transcription through c-Myc modulating intestinal epithelial barrier function

Polyamines regulate E-cadherin transcription through c-Myc modulating intestinal epithelial barrier function

Downregulation of KLF6 is an early event in hepatocarcinogenesis, and stimulates proliferation while reducing differentiation

The Slit/Robo System Suppresses Hepatocyte Growth Factor-dependent Invasion and Morphogenesis

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