Histone deacetylase inhibition suppresses the transforming growth factor β1-induced epithelial-to-mesenchymal transition in hepatocytes

Kaimori, Aki; Potter, James J.; Choti, Michael A.; Ding, Zhen; Mezey, Esteban; Koteish, Ayman

doi:10.1002/hep.23765

Cited by 82 publications

(67 citation statements)

References 52 publications

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“…5,15 TGF-β-induced hepatocyte EMT and EMTinduced fibrosis could be attenuated by histone deacetylase inhibitor via epigenetic modulation of type I collagen. 26 However, there were also data challenging the concept that hepatocytes in vivo acquire a mesenchymal phenotype through EMT to produce ECM components in liver fibrosis in mice. 7 These divergent findings could be due to the failure to rigorously define EMT with specific and convincing markers.…”

Section: Curcumin Inhibits Emt In Human Hepatocytesmentioning

confidence: 99%

Curcumin inhibits cobalt chloride-induced epithelial-to-mesenchymal transition associated with interference with TGF-β/Smad signaling in hepatocytes

Kong

Zhang

Shao

et al. 2015

Laboratory Investigation

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Epithelial-mesenchymal transition (EMT) occurs during adult tissue remodeling responses including carcinogenesis and fibrosis. Existing evidence reveals that hepatocytes can undergo EMT in adult liver, which is critically involved in chronic liver injury. We herein established a hypoxia-induced EMT model in human LO2 hepatocytes treated with cobalt chloride (CoCl 2 ) in vitro, and evaluated the effects of curcumin, a natural antifibrotic compound, on hepatocyte EMT and explored the underlying molecular mechanisms. We found that CoCl 2 at non-toxic doses induced a mesenchymal cell phenotype in hepatocytes and upregulated several mesenchymal markers including α-smooth muscle actin, vimentin, N-cadherin, fibronectin and Snail (an EMT-related transcription factor), but downregulated the epithelial marker E-cadherin in hepatocytes. However, curcumin reversed the morphological changes, abrogated the increased expression of mesenchymal markers, and rescued E-cadherin expression in CoCl 2 -treated hepatocytes, suggesting the inhibition of hepatocyte EMT in vitro. We further found that curcumin interfered with the transforming growth factor-β (TGF-β) signaling by reducing the expression of TGF-β receptor I and inhibiting the expression and phosphorylation of Smad2 and Smad3. Use of SB431542, a specific inhibitor of TGF-β receptor I, demonstrated that interference with the TGF-β/Smad pathway was associated with curcumin suppression of hepatocyte EMT. Our in vivo data showed that curcumin affected hepatic EMT in rat fibrotic liver caused by carbon tetrachloride, which was associated with the inhibition of TGF-β/Smad signaling. These findings characterized a novel mechanism by which curcumin modulated hepatocyte EMT implicated in treatment of liver fibrosis.

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Section: Curcumin Inhibits Emt In Human Hepatocytesmentioning

confidence: 99%

Curcumin inhibits cobalt chloride-induced epithelial-to-mesenchymal transition associated with interference with TGF-β/Smad signaling in hepatocytes

Kong

Zhang

Shao

et al. 2015

Laboratory Investigation

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“…TSA also exerted anti-EMT effects reflected by the preservation of epithelial markers (E-cadherin and albumin) and reversal of EMT-induced fibrosis. These effects seem to rely on epigenetic modulation of type I collagen by deactivating the mothers against decapentaplegic homolog 3 (Smad3)/Smad4 transcription complex and preventing p300 bind to Smad3 [67].…”

Section: New and Emerging Hdac Inhibitors For Liver Fibrosis Treatmentmentioning

confidence: 99%

Epigenetic modifications by histone deacetylases: Biological implications and therapeutic potential in liver fibrosis

et al. 2015

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“…For example, an HDAC inhibitor could induce the expression of differentiation marker proteins, morphological change, and functional cytodifferentiation in both human endometrial stromal and epithelial cells (Uchida et al, 2006). In addition, trichostatin A (TSA) preserved E-cadherin gene expression via inhibition of EMT in hepatocytes (Kaimori et al, 2010) and renal proximal tubular epithelial cells (Yoshikawa et al, 2007). However, it is unclear whether a HDAC inhibitor is able to stimulate mesenchymal-like progenitors to restore the expression of epithelial features.…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Induces the Expression of Select Epithelial Genes in Mouse Utricle Sensory Epithelia-Derived Progenitor Cells

Wang

2014

Cellular Reprogramming

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Mouse utricle sensory epithelial cell-derived progenitor cells (MUCs), which have hair cell progenitor and mesenchymal features via epithelial-to-mesenchymal transition (EMT) as previously described, provide a potential approach for hair cell regeneration via cell transplantation. In this study, we treated MUCs with trichostatin A (TSA) to determine whether histone deacetylase inhibitor is able to stimulate the expression of epithelial genes in MUCs, an essential step for guiding mesenchymal-like MUCs to become sensory epithelial cells. After 72 h of TSA treatment, MUCs acquired epithelial-like features, which were indicated by increased expression of epithelial markers such as Cdh1, Krt18, and Dsp. Additionally, TSA decreased the expression of mesenchymal markers, including Zeb1, Zeb2, Snai1, and Snai2, and prosensory genes Lfng, Six1, and Dlx5. Moreover, the expression of the hair cell genes Atoh1 and Myo6 was increased in TSA-treated MUCs. We also observed significantly decreased expression of Hdac2 and Hdac3 in TSA-treated MUCs. However, no remarkable change was detected in protein expression using immunofluorescence, indicating that TSA-induced HDAC inhibition may contribute to the initial stage of the mesenchymal-to-epithelial phenotypic change. In the future, more work is needed to induce hair cell regeneration using inner ear tissue-derived progenitors to achieve an entire mesenchymal-to-epithelial transition.

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Histone deacetylase inhibition suppresses the transforming growth factor β1-induced epithelial-to-mesenchymal transition in hepatocytes

Cited by 82 publications

References 52 publications

Curcumin inhibits cobalt chloride-induced epithelial-to-mesenchymal transition associated with interference with TGF-β/Smad signaling in hepatocytes

Curcumin inhibits cobalt chloride-induced epithelial-to-mesenchymal transition associated with interference with TGF-β/Smad signaling in hepatocytes

Epigenetic modifications by histone deacetylases: Biological implications and therapeutic potential in liver fibrosis

Histone Deacetylase Inhibitor Induces the Expression of Select Epithelial Genes in Mouse Utricle Sensory Epithelia-Derived Progenitor Cells

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