Inhibition of Histone Deacetylase Activity Suppresses Epithelial-to-Mesenchymal Transition Induced by TGF-β1 in Human Renal Epithelial Cells

Yoshikawa, Masahide; Hishikawa, Keiichi; Marumo, Takeshi; Fujita, Toshiro

doi:10.1681/asn.2005111187

Cited by 192 publications

(189 citation statements)

References 40 publications

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“…(b) Protein levels of p27 were determined by immunoblotting with GAPDH used as a loading control. (Kim et al, 2001;Mehnert and Kelly, 2007;Yoshikawa et al, 2007). In prostate cancer, HDAC-1 overexpression has been noted in three different studies (Patra et al, 2001;Halkidou et al, 2004;Weichert et al, 2008a).…”

Section: Discussionmentioning

confidence: 97%

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

et al. 2009

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Section: Discussionmentioning

confidence: 97%

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

et al. 2009

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Section: Discussionmentioning

confidence: 99%

“…In addition, although we used sodium butyrate primarily to suppress HIF, it is also possible that the effect of sodium butyrate is not solely mediated via repression of HIF. For example HDAC modulate the function of other transcription factors including the repressor SNAIL1 (Peinado et al, 2004), and HDAC inhibitors have been shown to prevent TGF-␤-mediated EMT in renal tubular cells in vitro (Yoshikawa et al, 2007).In summary, VHL inactivation in the kidney epithelium triggers a down-regulation of cell-cell adhesion molecules involved in both AJs and TJs, which results in a dismantling of intercellular junctions and EMT. Further understanding as to how VHL loss-of-function achieves this, and the role of HIF, will be important in understanding the role of VHL in normal renal epithelium.…”

mentioning

confidence: 99%

Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin

Harten

Shukla

Barod

et al. 2009

MBoC

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Epithelial-to-mesenchymal transitions (EMT) are important in renal development, fibrosis, and cancer. Loss of function of the tumor suppressor VHL leads to many features of EMT, and it has been hypothesized that the pivotal mediator is down-regulation of the adherens junction (AJ) protein E-cadherin. Here we show that VHL loss-of-function also has striking effects on the expression of the tight junction (TJ) components occludin and claudin 1 in vitro in VHL-defective clear cell renal cell carcinoma (CCRCC) cells and in vivo in VHL-defective sporadic CCRCCs (compared with normal kidney). Occludin is also down-regulated in premalignant foci in kidneys from patients with germline VHL mutations, consistent with a contribution to CCRCC initiation. Reexpression of E-cadherin was sufficient to restore AJ but not TJ assembly, indicating that the TJ defect is independent of E-cadherin down-regulation. Additional experiments show that activation of hypoxia inducible factor (HIF) contributes to both TJ and AJ abnormalities, thus the VHL/HIF pathway contributes to multiple aspects of the EMT phenotype that are not interdependent. Despite the independent nature of the defects, we show that treatment with the histone deacetylase inhibitor sodium butyrate, which suppresses HIF activation, provides a method for reversing EMT in the context of VHL inactivation. INTRODUCTIONA key characteristic of epithelial surfaces is the formation of specialized intercellular junctions at points of cell-cell contact. It is increasingly appreciated that these junctions have extensive roles beyond their function in cellular cohesion including determination of epithelial permeability and providing inputs modulating proliferation and differentiation. Two important types of intercellular junctions in the kidney epithelium are the tight junction (TJ) and adherens junction (AJ; Tsukita et al., 2001;Conacci-Sorrell et al., 2002;Matter and Balda, 2003). AJs are formed on the basolateral cell membrane and are composed of transmembrane cadherins linked to intracellular catenin proteins (Conacci-Sorrell et al., 2002). AJs are involved in cell-cell adhesion and also regulate ␤-catenin availability (Nelson and Nusse, 2004). TJs are formed on the apical surface of the lateral membrane and are analagous in structure to AJs, with specific transmembrane proteins (occludin and claudins), which are linked to the actin cytoskeleton via intracellular adaptor proteins, the zona occludens (ZO) family of proteins (Tsukita et al., 2001). In addition to its traditional roles in maintaining apical-basal polarity and controlling paracellular permeability the TJ is also now recognized as a signaling hub. TJ regulation of pathways involving raf kinase, rho GTPase, and the Y-box transcription factor ZONAB control important cellular processes such as cell proliferation, gene transcription, and cellular differentiation (Braga, 2002;Matter and Balda, 2003;Gonzalez-Mariscal et al., 2007;Guillemot et al., 2008).VHL is a classical tumor suppressor gene which acts as a gatekeeper i...

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“…In addition, a significant proportion is derived from EMT of tubule epithelial cells. The importance of EMT has been demonstrated in experimental models, where blockade of EMT attenuates renal fibrosis (16,17).…”

Section: The Epithelial-to-mesenchymal Transition In Renal Tubular Cellsmentioning

confidence: 99%

Proximal tubular dysfunction as an indicator of chronic graft dysfunction

Câmara¹,

Williams

Pacheco-Silva³

2009

Braz J Med Biol Res

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New strategies are being devised to limit the impact of renal sclerosis on graft function. Individualization of immunosuppression, specifically the interruption of calcineurin-inhibitors has been tried in order to promote better graft survival once chronic graft dysfunction has been established. However, the long-term impact of these approaches is still not totally clear. Nevertheless, patients at higher risk for tubular atrophy and interstitial fibrosis (TA/IF) development should be carefully monitored for tubular function as well as glomerular performance. Since tubular-interstitial impairment is an early event in TA/IF pathogenesis and associated with graft function, it seems reasonable that strategies directed at assessing tubular structural integrity and function would yield important functional and prognostic data. The measurement of small proteins in urine such as α-1-microglobulin, Nacetyl-beta-D-glucosaminidase, alpha/pi S-glutathione transferases, β-2 microglobulin, and retinol binding protein is associated with proximal tubular cell dysfunction. Therefore, its straightforward assessment could provide a powerful tool in patient monitoring and ongoing clinical assessment of graft function, ultimately helping to facilitate longer patient and graft survival associated with good graft function.

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Inhibition of Histone Deacetylase Activity Suppresses Epithelial-to-Mesenchymal Transition Induced by TGF-β1 in Human Renal Epithelial Cells

Cited by 192 publications

References 40 publications

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin

Proximal tubular dysfunction as an indicator of chronic graft dysfunction

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