Regulation of E-cadherin Expression by <i>VHL</i> and Hypoxia-Inducible Factor

Esteban, Miguel A.; Tran, Maxine; Harten, Sarah K.; Hill, Peter; Castellanos, María C.; Chandra, Ashish; Raval, Raju R.; O’Brien, Tim; Maxwell, Patrick H.

doi:10.1158/0008-5472.can-05-2670

Cited by 245 publications

(227 citation statements)

References 33 publications

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“…TWIST1 may also regulate the expression of the bHLH repressor SNAIL that acts as a boundary repressor by downregulating the expression of ectodermal genes within the mesoderm (Ip et al, 1992). The HIF pathway can also regulate E-Cadherin repression, presumably via SNAIL (Esteban et al, 2006). Our data suggest that this might be in concert with TWIST1.…”

Section: Twist1 Is a Target Of Hif-2a Eh Gort Et Almentioning

confidence: 69%

The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2α

et al. 2007

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Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that play a crucial role in oxygen homeostasis. Intratumoral hypoxia and genetic alterations lead to HIF activity, which is a hallmark of solid cancer and is associated with poor clinical outcome. HIF activity is regulated by an evolutionary conserved mechanism involving oxygen-dependent HIFa protein degradation. To identify novel components of the HIF pathway, we performed a genome-wide RNA interference screen in Caenorhabditis elegans, to suppress HIF-dependent phenotypes, like egg-laying defects and hypoxia survival. In addition to hif-1 (HIFa) and aha-1 (HIFb), we identified hlh-8, gska-3 and spe-8. The hlh-8 gene is homologous to the human oncogene TWIST1. We show that TWIST1 expression in human cancer cells is enhanced by hypoxia in a HIF-2a-dependent manner. Furthermore, intronic hypoxia response elements of TWIST1 are regulated by HIF-2a, but not HIF-1a. These results identify TWIST1 as a direct target gene of HIF-2a, which may provide insight into the acquired metastatic capacity of hypoxic tumors.

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Section: Twist1 Is a Target Of Hif-2a Eh Gort Et Almentioning

confidence: 69%

The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2α

et al. 2007

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“…14 Recently, VHL was shown to promote the transcription of E-cadherin via HIF-dependent activation of E-cadherin-specific transcriptional repressors. [15][16][17] Thus, a loss of VHL in CC-RCC results in the hyperactivation of HIF that triggers the expression of E-cadherin repressors, which in turn attenuates the expression of E-cadherin. 15-17 E-cadherin, a homophilic adhesion molecule associated with catenins that functions as a major component of cell junctions in polarized epithelial cells, is an established tumor suppressor.…”

mentioning

confidence: 99%

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Gervais

Henry

Saravanan

et al. 2007

Laboratory Investigation

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The loss of functional von Hippel-Lindau (VHL) tumor suppressor gene is associated with the development of clear-cell renal cell carcinoma (CC-RCC). Recently, VHL was shown to promote the transcription of E-cadherin, an adhesion molecule whose expression is inversely correlated with the aggressive phenotype of numerous epithelial cancers. Here, we performed immunohistochemistry on CC-RCC tissue microarrays to determine the prognostic value of E-cadherin and VHL with respect to Fuhrman grade and clinical prognosis. Low Fuhrman grade and good prognosis associated with positive VHL and E-cadherin immunoreactivity, whereas poor prognosis and high-grade tumors associated with a lack of E-cadherin and lower frequency of VHL staining. A significant portion of CC-RCC with positive VHL immunostaining correlated with nuclear localization of C-terminally cleaved E-cadherin. DNA sequencing revealed in a majority of nuclear E-cadherin-positive CC-RCC, subtle point mutations, deletions and insertions in VHL. Furthermore, nuclear E-cadherin was not observed in chromophobe or papillary RCC, as well as matched normal kidney tissue. In addition, nuclear E-cadherin localization was recapitulated in CC-RCC xenografts devoid of functional VHL or reconstituted with synthetic mutant VHL grown in SCID mice. These findings provide the first evidence of aberrant nuclear localization of E-cadherin in CC-RCC harboring VHL mutations, and suggest potential prognostic value of VHL and E-cadherin in CC-RCC. [4][5][6][7] Currently, a prediction of patient survival is based on traditional clinical parameters, including tumor size and Fuhrman nuclear grade. 8 However, the emerging understanding of the molecular pathways implicated in CC-RCC genesis and progression is providing previously unappreciated markers, which may serve as additional or better prognostic indicators of CC-RCC.The principal cause of sporadic CC-RCC and familial von Hippel-Lindau (VHL) disease-associated CC-RCC is the inactivating mutations of VHL. Although VHL patients also develop tumors in other organs including the central nervous system, retina and the adrenal gland, CC-RCC remains to be the leading cause of morbidity and death for VHL patients. 9 The most well-established function of VHL is its role in the oxygen-dependent negative regulation of hypoxia-inducible factor (HIF). VHL is a substrate-conferring component of an E3 ubiquitin ligase ECV (elongins/Cul2/VHL) that polyubiquitylates the catalytic a-subunit of HIF that has undergone hydroxylation on conserved prolyl residues within the oxygen-dependent degradation (ODD) domain. Prolyl hydroxylation is mediated by a class of prolyl hydroxylases (PHD1-3) in an oxygen-dependent manner. Thus, under hypoxia or in the absence of a functional VHL, HIFa becomes stabilized and binds to its common and constitutively expressed b-subunit, forming an active HIF transcription factor capable of transactivating numerous hypoxia-inducible genes such as vascular endothelial growth factor (VEGF),

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“…Interestingly, the transcriptional repressors of E-cadherin, namely, Snail, Slug, Twist, Zeb1 and Zeb2, can be regulated by hypoxia in human cancer. In VHL-deficient renal cell carcinoma, stable expression of the HIF-1α and HIF-2α isoforms is associated with increased expression of Snail, Zeb1 and Zeb2, loss of E-cadherin and an increase in invasion [69,70]. Twist, a master regulator of gastrulation and mesoderm specification, is also essential in mediating cancer metastasis and can be directly regulated by both HIF-1α and HIF-2α [71,72].…”

Section: Inflammation Creates a Hypoxic Microenvironmentmentioning

confidence: 99%

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

Heinrich

Walser

Krysan

et al. 2011

Cancer Microenvironment

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The inflammatory tumor microenvironment (TME) has many roles in tumor progression and metastasis, including creation of a hypoxic environment, increased angiogenesis and invasion, changes in expression of microRNAs (miRNAs) and an increase in a stem cell phenotype. Each of these has an impact on epithelial mesenchymal transition (EMT), particularly through the downregulation of E-cadherin. Here we review seminal work and recent findings linking the role of inflammation in the TME, EMT and lung cancer initiation, progression and metastasis.Finally, we discuss the potential of targeting aspects of inflammation and EMT in cancer prevention and treatment.

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Regulation of E-cadherin Expression by VHL and Hypoxia-Inducible Factor

Cited by 245 publications

References 33 publications

The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2α

The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2α

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

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