Therapeutic activity of the histone deacetylase inhibitor SB939 on renal fibrosis

Kang, Sung Goo; Lee, Soung-Min; Kim, Joo-Yong; Kim, Soyeon; Kim, Yeong-Hoon; Kim, Tae-Hee; Kang, Mi Sun; Jang, Wonhee; Seo, Su‐Kil

doi:10.1016/j.intimp.2016.11.008

Cited by 14 publications

(9 citation statements)

References 24 publications

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“…BRD4) (Tang et al, 2013) and EZH2 (Coward et al, 2018;Xiao et al, 2016) were identified. We chose to focus on pracinostat because it was most effective in our primary assay outcome, and because HDAC inhibition has proven effective in fibrosis models (Barter et al, 2010;Bombardo et al, 2018;Conforti et al, 2017;Glenisson et al, 2007;Guo et al, 2009;Kang et al, 2017;Khalil et al, 2015;Kim et al, 2018;Ota et al, 2015) but its anti-fibrotic effects remain poorly understood. However, we also note that inhibitors of several enzymes not previously linked to fibrosis were identified in our screen, such as L3MBTL3, a reader of methylated-lysine on histones (Min et al, 2007;Trojer et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…The most effective compound at the 2.5 μM dosing, and amongst the most effective at 0.5 μM dosing, was pracinostat, an HDAC inhibitor (panHDAC except HDAC6), which is known to attenuate experimental renal fibrosis (Kang et al, 2017). HDACs primarily function by catalyzing the de-acetylation of histones resulting in gene repression; thus, inhibition of HDACs should result in an increase in transcriptional activity.…”

Section: Identification Of Pracinostat As a Potent Attenuator Of Humamentioning

confidence: 99%

“…HDACs primarily function by catalyzing the de-acetylation of histones resulting in gene repression; thus, inhibition of HDACs should result in an increase in transcriptional activity. Interestingly, while there is widespread evidence that HDAC inhibitors are effective in both in vitro and in vivo fibrosis models (Barter et al, 2010;Bombardo et al, 2018;Conforti et al, 2017;Glenisson et al, 2007;Guo et al, 2009;Kang et al, 2017;Khalil et al, 2015;Kim et al, 2018), there is a lack of understanding of how HDAC inhibition reduces fibroblast activation and fibrosis. Moreover, while several HDAC inhibitors were highly effective at reducing αSMA in our screen, others were less so (entinostat and tacedinaline), while still others actually enhanced the level of αSMA (CS-055, RSC133 and TC-H 106), highlighting the fact that specific HDACs and HDAC inhibitors likely act via distinct targets and mechanisms to regulate fibroblast biology.…”

Section: Identification Of Pracinostat As a Potent Attenuator Of Humamentioning

confidence: 99%

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TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

Jones

Haak

Caporarello

et al. 2019

Journal of Cell Science

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Tissue fibrosis is a chronic disease driven by persistent fibroblast activation that has recently been linked to epigenetic modifications. Here, we screened a small library of epigenetic small-molecule modulators to identify compounds capable of inhibiting or reversing TGFβ-mediated fibroblast activation. We identified pracinostat, an HDAC inhibitor, as a potent attenuator of lung fibroblast activation and confirmed its efficacy in patient-derived fibroblasts isolated from fibrotic lung tissue. Mechanistically, we found that HDAC-dependent transcriptional repression was an early and essential event in TGFβmediated fibroblast activation. Treatment of lung fibroblasts with pracinostat broadly attenuated TGFβ-mediated epigenetic repression and promoted fibroblast quiescence. We confirmed a specific role for HDAC-dependent histone deacetylation in the promoter region of the anti-fibrotic gene PPARGC1A (PGC1α) in response to TGFβ stimulation. Finally, we identified HDAC7 as a key factor whose siRNA-mediated knockdown attenuates fibroblast activation without altering global histone acetylation. Together, these results provide novel mechanistic insight into the essential role HDACs play in TGFβmediated fibroblast activation via targeted gene repression.

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Section: Discussionmentioning

confidence: 99%

Section: Identification Of Pracinostat As a Potent Attenuator Of Humamentioning

confidence: 99%

Section: Identification Of Pracinostat As a Potent Attenuator Of Humamentioning

confidence: 99%

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TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

Jones

Haak

Caporarello

et al. 2019

Journal of Cell Science

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“…In addition, HDAC inhibitor SB939 inhibited EMT of human renal proximal tubular epithelial cells, and reduced the accumulation of α-SMA and inflammatory and pro-fibrotic cytokines. The mechanism maybe due to the inhibition of Smad-independent TGF-β signaling by HDAC inhibitor and involve MAPK and PI3K/AKT pathways [25]. Apart from being an ER stress inhibitor, 4PBA also acts as an HDAC inhibitor (class I and II) when used at higher doses.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylases Promote ER Stress Induced Epithelial Mesenchymal Transition in Human Lung Epithelial Cells

Liu¹,

Zhu²,

Gong³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Epithelial to mesenchymal transition (EMT) is a crucial process involved in pulmonary fibrosis. This study aimed to explore the role of histone deacetylases (HDACs) and endoplasmic reticulum (ER) stress in EMT in human lung epithelial cells. Methods: Human lung adenocarcinoma A549 cells were treated with bleomycin and tunicamycin to induce EMT. The proliferation of A549 cells was detected by MTT assay. The expression of HDACs and EMT markers was detected by PCR and Western blot analysis. The secretion of TGF-β1 and collagen I was examined by ELISA. Results: A549 cells switched from a cobblestone-like appearance to an elongated fibroblast like appearance after exposure to tunicamycin or bleomycin, accompanied by increased expression of N-cadherin, α-SMA and Collagen I. Meanwhile, GRP78 was upregulated in A549 cells exposed to tunicamycin or bleomycin. These changes induced by tunicamycin or bleomycin could be abrogated by 4-PBA. Moreover, tunicamycin and bleomycin promoted the expression of HDAC2 and HDAC6, and HDACs inhibitor SAHA abrogated the morphological and biochemical changes in A549 cells. 4-PBA and SAHA inhibited the upregulation of pulmonary fibrosis factors TGF-β1 and IL-32 and the activation of Smad pathway induced by tunicamycin or bleomycin. Conclusions: We provide the first evidence that tunicamycin and bleomycin induce ER stress and EMT in lung epithelial cells via the upregulation of HDACs. HDACs inhibitor could inhibit ER stress induced upregulation of pulmonary fibrosis factors and the activation of Smad pathway. HDACs inhibitors are promising agents for the therapy of pulmonary fibrosis.

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“…Among them, Pracinostat 1 is a promising compound, which has been granted breakthrough therapy designation by FDA for the treatment of patients with newly diagnosed acute myelocytic leukemia (AML) who are ≥75 years of age or unfit for intensive chemotherapy(Abaza et al., ; Garcia‐Manero et al., ). Currently, Pracinostat is undergoing phase III clinical trials (Abaza et al., ; Ganai, ; Garcia‐Manero et al., ; Kang et al., ; Novotny‐Diermayr et al., ).…”

Section: Introductionmentioning

confidence: 99%

Minor structural modifications to Pracinostat produce big changes in its biological responses

et al. 2019

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A series of compounds similar to Pracinostat that contained benzimidazole ring and N-hydroxyacrylamide attached at 5-or 6-position were designed, synthesized, and evaluated as HDAC inhibitors. It was interesting to find that the corresponding derivative 1 with N-hydroxyacrylamide attached at 5-position was a potent HDAC inhibitor while the others at 6-position were not. This is the first time to demonstrate the position difference plays important role in the HDAC inhibitory activities of the cinnamic hydroxamates. K E Y W O R D S HDAC inhibitors, histone deacetylases, hydroxamic acids, Pracinostat, synthesisThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Therapeutic activity of the histone deacetylase inhibitor SB939 on renal fibrosis

Cited by 14 publications

References 24 publications

TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

Histone Deacetylases Promote ER Stress Induced Epithelial Mesenchymal Transition in Human Lung Epithelial Cells

Minor structural modifications to Pracinostat produce big changes in its biological responses

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