Regulation of Gene Expression by Sodium Valproate in Epithelial-to-Mesenchymal Transition

Noguchi, Shuhei; Eitoku, Masamitsu; Moriya, Shigeharu; Kondo, Shinji; Kiyosawa, Hidenori; Watanabe, Takashi; Suganuma, Narufumi

doi:10.1007/s00408-015-9776-9

Cited by 25 publications

(20 citation statements)

References 44 publications

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“…HDAC inhibitor (HDACi) drugs, romidepsin [155], trichostatin A [156, 157], suberoylanilide hydroxamic acid [123, 158], sodium valproate [159], panobinostat [160, 161], and valproic acid [162, 163], have all been shown to suppress fibrosis. In a standard animal model of cutaneous radiation syndrome, application of topical formulations of phenylbutyrate, an HDACi [164] and oxidative stress inhibitor [165–167], reduced acute skin damage and protected from late radiation-induced effects, such as fibrosis and tumor formation [168].…”

Section: Ros-mediated Histone Modification Changes In Rifmentioning

confidence: 99%

Reactive Oxygen Species Drive Epigenetic Changes in Radiation-Induced Fibrosis

Shrishrimal

Kosmacek

Oberley‐Deegan

2019

Oxidative Medicine and Cellular Longevity

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Radiation-induced fibrosis (RIF) develops months to years after initial radiation exposure. RIF occurs when normal fibroblasts differentiate into myofibroblasts and lay down aberrant amounts of extracellular matrix proteins. One of the main drivers for developing RIF is reactive oxygen species (ROS) generated immediately after radiation exposure. Generation of ROS is known to induce epigenetic changes and cause differentiation of fibroblasts to myofibroblasts. Several antioxidant compounds have been shown to prevent radiation-induced epigenetic changes and the development of RIF. Therefore, reviewing the ROS-linked epigenetic changes in irradiated fibroblast cells is essential to understand the development and prevention of RIF.

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Section: Ros-mediated Histone Modification Changes In Rifmentioning

confidence: 99%

Reactive Oxygen Species Drive Epigenetic Changes in Radiation-Induced Fibrosis

Shrishrimal

Kosmacek

Oberley‐Deegan

2019

Oxidative Medicine and Cellular Longevity

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“…Other mechanisms may also exist that mediate the VPA-regulated EMT process. Noguchi et al (38) revealed that histone modification correlated with EMT. It is reasonable to make a connection between different media proteins and EMT regulation.…”

Section: Smad4 Expression Tif1-γ Expression -------------------------mentioning

confidence: 99%

Valproic acid inhibits epithelial-mesenchymal transition in renal cell carcinoma by decreasing SMAD4 expression

Mao

Lan

Yuan

et al. 2017

Molecular Medicine Reports

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Renal cell carcinoma (RCC) is the most common malignancy in urogenital neoplasms worldwide. According to previous studies, valproic acid (VPA), an anticonvulsant drug, can suppress tumor metastasis and decrease the expression level of Mothers against decapentaplegic homolog 4 (SMAD4) and therefore may inhibit epithelial‑mesenchymal transition (EMT), which is responsible for cancer metastasis. However, the association between VPA, EMT and SMAD4 in RCC metastasis remains obscure. In the present study, it was demonstrated that in the RCC cell lines 786‑O and Caki‑1 treated with VPA, the neural (N)‑cadherin, vimentin and SMAD4 protein and mRNA levels were decreased, accompanied with an increase in expression of epithelial (E)‑cadherin. Silencing SMAD4 expression decreased the expression of EMT markers, including N‑cadherin and simultaneously upregulated E‑cadherin in RCC cell lines. SMAD4 overexpression counteracted the VPA‑mediated EMT‑inhibitory effect (P<0.05). The present study demonstrates that VPA inhibited EMT in RCC cells via altering SMAD4 expression. In addition, immunohistochemical staining demonstrated that transforming growth factor‑β (TGF‑β) and low expression of SMAD4 was associated with a lower Fuhrman grade and low expression of transcription intermediary factor 1‑γ was associated with a higher tumor Fuhrman grade (P<0.05), Therefore, based on the regulatory effect of SMAD4 on EMT‑associated transcription factors, SMAD4 which can form a SMAD3/SMAD4 complex induced by TGF‑β, could be a potential anticancer drug target inhibiting tumor invasion and metastasis in RCC.

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“…These results suggested that the process of fibrosis had been initiated in terms of the gene expression profile but not on the histopathological features in early indium lung. The expression of several epithelial or mesenchymal marker genes, such as Cdh1 or Acta2, was not changed suggesting that epithelial-to-mesenchymal transition, a key phenomenon in fibrogenesis (Kalluri & Weinberg, 2009;Noguchi et al, 2015), had not occurred or was undetectable, possibly due to RNA extraction from the whole lung. In histopathology, there were no collagen accumulation characteristics of pulmonary fibrosis, and there were no cholesterol clefts, observed in many human indium lung cases (Cummings et al, 2012), and observed in long-term observation of ITO-or indium oxide-treated hamsters (Tanaka et al, 2010).…”

Section: Discussionmentioning

confidence: 85%

Fibrotic gene expression coexists with alveolar proteinosis in early indium lung

Noguchi

Eitoku

Kiyosawa

et al. 2016

Inhalation Toxicology

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Occupational inhalation of indium compounds can cause the so-called "indium lung disease". Most affected individuals show pulmonary alveolar proteinosis (PAP) and fibrotic interstitial lung disease. In animal experiments, inhalation of indium tin oxide or indium oxide has been shown to cause lung damage. However, the mechanisms by which indium compounds lead to indium lung disease remain unknown. In this study, we constructed a mouse model of indium lung disease and analyzed gene expression in response to indium exposure. Indium oxide (In2O3, 10 mg/kg, primary particle size <100 nm) was administered intratracheally to C57BL/6 mice (male, 8 weeks of age) twice a week for 8 weeks. Four weeks after the final instillation, histopathological analysis exhibited periodic acid-Schiff positive material in the alveoli, characteristic of PAP. Comprehensive gene expression analysis by RNA-Seq, however, revealed expression of fibrosis-related genes, such as surfactant associated protein D, surfactant associated protein A1, mucin 1, and collagen type I and III, was significantly increased, indicating that fibrotic gene expression progresses in early phase of indium lung. These data supported the latest hypothesis that PAP occurs as an acute phase response and is replaced by fibrosis after long-term latency.

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Regulation of Gene Expression by Sodium Valproate in Epithelial-to-Mesenchymal Transition

Abstract: Histone acetylation was down-regulated by TGF-β1 stimulation in A549 cells. VPA partially inhibited EMT and the decrease of histone acetylation, which plays an important role in the progression of EMT.

Cited by 25 publications

References 44 publications

Reactive Oxygen Species Drive Epigenetic Changes in Radiation-Induced Fibrosis

Reactive Oxygen Species Drive Epigenetic Changes in Radiation-Induced Fibrosis

Valproic acid inhibits epithelial-mesenchymal transition in renal cell carcinoma by decreasing SMAD4 expression

Fibrotic gene expression coexists with alveolar proteinosis in early indium lung

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