Metastatic Progression of Prostate Cancer and E-Cadherin

Putzke, Aaron P.; Ventura, Aviva P.; Bailey, Alexander M.; Akture, Canan; Opoku-Ansah, John; Çeliktaş, Müge; Hwang, Michael S.; Darling, Douglas S.; Coleman, Ilsa M.; Nelson, Peter S.; Nguyen, Holly M.; Corey, Eva; Tewari, Muneesh; Morrissey, Colm; Vessella, Robert L.; Knudsen, Beatrice S.

doi:10.1016/j.ajpath.2011.03.028

Cited by 133 publications

(134 citation statements)

References 58 publications

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“…Interestingly, however, we observed that Snai1 is expressed in the nucleus of mammary epithelial cells, but it does not repress ␤4 transcription. This observation is consistent with other reports of Snai1 expression in epithelial cells (16)(17)(18). Aside from the possibility that Snai1 can be excluded from the nucleus (19), it is not known why nuclear Snai1 does not repress genes in epithelial cells.…”

supporting

confidence: 82%

Id2 Complexes with the SNAG Domain of Snai1 Inhibiting Snai1-Mediated Repression of Integrin β4

Chang

Yang

Pursell

et al. 2013

Molecular and Cellular Biology

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The epithelial-mesenchymal transition (EMT) is a fundamental process that underlies development and cancer. Although the EMT involves alterations in the expression of specific integrins that mediate stable adhesion to the basement membrane, such as ␣6␤4, the mechanisms involved are poorly understood. Here, we report that Snai1 inhibits ␤4 transcription by increasing repressive histone modification (trimethylation of histone H3 at K27 [H3K27Me3]). Surprisingly, Snai1 is expressed and localized in the nucleus in epithelial cells, but it does not repress ␤4. We resolved this paradox by discovering that Id2 complexes with the SNAG domain of Snai1 on the ␤4 promoter and constrains the repressive function of Snai1. Disruption of the complex by depleting Id2 resulted in Snai1-mediated ␤4 repression with a concomitant increase in H3K27Me3 modification on the ␤4 promoter. These findings establish a novel function for Id2 in regulating Snai1 that has significant implications for the regulation of epithelial gene expression. The regulated expression of specific integrins is a fundamental component of development, tissue homeostasis, and many diseases (1). A prime example of this concept is the regulation of epithelial integrins, which function primarily in the anchoring of epithelial cells to laminins in the basement membrane (2). Developmental and pathological processes that necessitate epithelial cell migration often involve disruption of the stable adhesive contacts provided by integrins (3-5). The two major integrins that anchor epithelial cells to basement membrane laminins are ␣3␤1 and ␣6␤4 (6-9), and stimuli that disrupt epithelial adhesion frequently target the expression, localization, and cytoskeletal interactions of ␣6␤4 (3, 4, 10-12). The epithelial-mesenchymal transition (EMT) provides a useful model system for studying the regulation of epithelial integrins. Although studies on the EMT have focused largely on mechanisms that disrupt cell-cell adhesions (13, 14), disruption of integrin-mediated anchoring to matrix is an important component of the EMT, but the mechanisms involved are poorly understood.The EMT of normal mammary epithelial cells involves transcriptional repression of the ␤4 integrin subunit (referred to as ␤4), which results in loss of the ␣6␤4 integrin (15). This repression is associated with a decrease in active histone modifications (acetylation of histone H3 at K9 [H3K9Ac] and trimethylation of histone H3 at K4 [H3K4Me3]) and an increase in repressive histone modification (H3K27Me3) on the ␤4 promoter (15). Although these previous observations provide a foundation for understanding how ␤4 is regulated during the EMT, little is known about the mechanisms involved. For example, are specific transcription factors involved in ␤4 repression, and, if so, what is their relationship to epigenetic modifications? Our pursuit of this problem in the current study revealed a key role for the zinc finger protein Snai1 in repressing ␤4. Interestingly, however, we observed that Snai1 is expressed in the nucl...

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supporting

confidence: 82%

Id2 Complexes with the SNAG Domain of Snai1 Inhibiting Snai1-Mediated Repression of Integrin β4

Chang

Yang

Pursell

et al. 2013

Molecular and Cellular Biology

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“…Similarly, maintenance of E-cadherin expression is not detrimental to invasion and metastasis. Maintenance of E-cadherin expression in highly metastatic cell lines has been described in a number of preclinical models of metastasis of breast (4T1), prostate (DU145), and bladder (TSU-Pr1) cancers [40][41][42]. In this study, we examined the down-regulation of E-cadherin in MDA-treated 4T-1 cells and tumor tissue.…”

Section: Discussionmentioning

confidence: 97%

Meso-dihydroguaiaretic acid induces apoptosis and inhibits cell migration via p38 activation and EGFR/Src/intergrin β3 downregulation in breast cancer cells

et al. 2015

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“…Although WT1 has been proposed to regulate EMT by repressing E-cadherin; more recently, WT1 has been linked to the regulation of epicardial EMT through the β-catenin and retinoic acid signaling pathways (29). Interestingly, it has been found that WT1 transcriptionally activates Snail with partial maintenance of E-cadherin, and WT1 is associated with epithelial characteristics in kidney cells and in clear cell renal cell carcinoma (31). Thus, in these examples, WT1 induces an epithelial-mesenchymal hybrid transition defined by Snail upregulation with E-cadherin maintenance, a tumor cell differentiation state in which cancer cells retain both mesenchymal and epithelial features that may contribute to tumor cell plasticity and tumor progression (30).…”

Section: Developmental Expression Of Wt1mentioning

confidence: 99%

“…Thus, in these examples, WT1 induces an epithelial-mesenchymal hybrid transition defined by Snail upregulation with E-cadherin maintenance, a tumor cell differentiation state in which cancer cells retain both mesenchymal and epithelial features that may contribute to tumor cell plasticity and tumor progression (30). Similarly in prostate cancer (PC), a partial EMT with features of both epithelial and mesenchymal cells has been observed (31). The transformation of metanephric mesenchyme to epithelial cells within the condensing glomeruli also is similar to the metastatic process of cancer cells, whereby motile cancer cells, after extravasation, must revert back to their epithelial state to survive at the metastatic site (32).…”

Section: Developmental Expression Of Wt1mentioning

confidence: 99%

Functional Role of WT1 in Prostate Cancer

et al. 2016

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Licence: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source. AbstractAlthough initial discoveries of Wilms tumor 1 (WT1) expression in extrarenal disease generated controversy, we and others have examined WT1 expression in non-Wilms cancers and have demonstrated that the WT1(A) isoform, lacking the lysine-threonine-serine tripeptide (KTS) insertion, transcriptionally regulates the expression of growth control genes in other cancer types. Here, we review our evidence that WT1 is expressed in prostate cancer (PC) epithelial cells and regulates PC critical genes. That WT1 may promote metastatic disease is consistent with previous findings that WT1 suppressed E-cadherin and enhanced motility of PC cells with low migratory and metastatic potential. Recent findings led us to askFraizer et al. 236whether WT1 acts as an angiogenic switch in PC. Although vascular endothelial growth factor (VEGF) is regulated at several levels and by a number of different factors, a mechanistic understanding of WT1-mediated transcriptional regulation in PC cells was previously lacking. Here, we discuss the evidence of WT1-and androgen receptor (AR)-binding sites in the VEGF promoter and show the potential for cooperation between hormone and WT1. These findings revealed that in AR-intact PC cells, WT1 was sufficient to upregulate VEGF transcription, and WT1 expression enhanced the hormone activation of VEGF expression. This notion that WT1 can activate an angiogenic switch in PC cells, to enhance tumor growth and progression to metastatic disease, is consistent with our understanding of the oncogenic nature of WT1 overexpression in inappropriate tissues or at inappropriate times. The potential for WT1 to promote both tumor angiogenesis and PC cell migration suggests that WT1 regulates genes that promote PC progression to lethal metastatic disease. Therapies targeting WT1 in PC may reduce metastatic spread and increase overall survival.

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Metastatic Progression of Prostate Cancer and E-Cadherin

Cited by 133 publications

References 58 publications

Id2 Complexes with the SNAG Domain of Snai1 Inhibiting Snai1-Mediated Repression of Integrin β4

Id2 Complexes with the SNAG Domain of Snai1 Inhibiting Snai1-Mediated Repression of Integrin β4

Meso-dihydroguaiaretic acid induces apoptosis and inhibits cell migration via p38 activation and EGFR/Src/intergrin β3 downregulation in breast cancer cells

Functional Role of WT1 in Prostate Cancer

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