Requirement of Histone Deacetylase 6 for Interleukin-6 Induced Epithelial-Mesenchymal Transition, Proliferation, and Migration of Peritoneal Mesothelial Cells

Shi, Yingfeng; Tao, Min; Ni, Jun; Tang, Lunxian; Liu, Feng; Chen, Hui; Ma, Xiaoyan; Hu, Yan; Zhou, Xun; Qiu, Andong; Zhuang, Songlin; Liu, Na

doi:10.3389/fphar.2021.722638

Cited by 15 publications

(15 citation statements)

References 39 publications

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“…In our previous study, we found an elevated expression of HDAC6 in peritoneum and dialysis effluent from PD patients ( 29 ). Moreover, we demonstrated that HDAC6 was indispensable in interleukin-6 induced EMT, proliferation and migration of peritoneal mesothelial cells ( 30 ). However, the link between HDAC6 and M2 polarization in PF remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic Inhibition of Histone Deacetylase 6 Prevents the Progression of Chlorhexidine Gluconate-Induced Peritoneal Fibrosis by Blockade of M2 Macrophage Polarization

Shi

Li²,

Chen³

et al. 2022

Front. Immunol.

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Peritoneal fibrosis contributes to ultrafiltration failure in peritoneal dialysis (PD) patients and thus restricts the wide application of PD in clinic. Recently we have demonstrated that histone deacetylase 6 (HDAC6) is critically implicated in high glucose peritoneal dialysis fluid (HG-PDF) induced peritoneal fibrosis, however, the precise mechanisms of HDAC6 in peritoneal fibrosis have not been elucidated. Here, we focused on the role and mechanisms of HDAC6 in chlorhexidine gluconate (CG) induced peritoneal fibrosis and discussed the mechanisms involved. We found Tubastatin A (TA), a selective inhibitor of HDAC6, significantly prevented the progression of peritoneal fibrosis, as characterized by reduction of epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) protein deposition. Inhibition of HDAC6 remarkably suppressed the expression of matrix metalloproteinases-2 (MMP2) and MMP-9. Administration of TA also increased the expression of acetylation Histone H3 and acetylation α-tubulin. Moreover, our results revealed that blockade of HDAC6 inhibited alternatively M2 macrophages polarization by suppressing the activation of TGF-β/Smad3, PI3K/AKT, and STAT3, STAT6 pathways. To give a better understanding of the mechanisms, we further established two cell injured models in Raw264.7 cells by using IL-4 and HG-PDF. Our in vitro experiments illustrated that both IL-4 and HG-PDF could induce M2 macrophage polarization, as demonstrated by upregulation of CD163 and Arginase-1. Inhibition of HDAC6 by TA significantly abrogated M2 macrophage polarization dose-dependently by suppressing TGF-β/Smad, IL4/STAT6, and PI3K/AKT signaling pathways. Collectively, our study revealed that blockade of HDAC6 by TA could suppress the progression of CG-induced peritoneal fibrosis by blockade of M2 macrophage polarization. Thus, HDAC6 may be a promising target in peritoneal fibrosis treatment.

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Section: Introductionmentioning

confidence: 99%

Pharmacologic Inhibition of Histone Deacetylase 6 Prevents the Progression of Chlorhexidine Gluconate-Induced Peritoneal Fibrosis by Blockade of M2 Macrophage Polarization

Shi

Li²,

Chen³

et al. 2022

Front. Immunol.

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“…EMT is an important mechanism for migration and wound healing that can promote tumor progression ( 27 ). HDAC6 inhibition is proved to upregulate E-cadherin, a marker of EMT, making breast cancer cells or peritoneal mesothelial cells less susceptible to undergoing EMT ( 12 ). HDAC6 abrogation also reversed TGF-β-mediated EMT in breast cancer cells ( 12 ).…”

Section: Discussionmentioning

confidence: 99%

“…Besides, HDAC6 is highly expressed in estrogen receptor-positive breast cancer cells and accelerates the metastatic process of breast cancer by reducing the acetylation modification of α-tubulin, enhancing microtubule activity, and promoting cell adhesion and migration ( 9 , 11 ). In leukemia cells, HDAC6 inhibitors can inhibit the process of α-tubulin deacetylation by HDAC6, disrupting the microtubule dynamics system and ultimately inhibiting cancer cell migration ( 12 ). Furthermore, HDAC6 inhibition can block the process of proliferation and invasion of gastric cancer cells ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

Canagliflozin, characterized as a HDAC6 inhibitor, inhibits gastric cancer metastasis

Jiang

2022

Front. Oncol.

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Gastric cancer is a common gastrointestinal cancer. Survival outcome for patients with the recurrence or metastasis remains poor due to the lack of effective targeting drugs. The mechanisms of non-histone acetylation modifications are key epigenetic regulations that participate in various biological processes. HDAC6 is mostly located in the cytoplasm to deacetylate non-histone substrates, which has been identified as a critical promoter of many oncogenic pathways in cancers, including gastric cancer. Nevertheless, its inhibitor has not been applied in gastric cancer clinically. In this study, we identified canagliflozin as an active HDAC6-targeted inhibitor from FDA-approved Drug Library by enzymatic assay. The strong affinity of the compounds with HDAC6 was further verified by surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA). In addition, molecular docking showed that canagliflozin could bind to the active pocket of HDAC6 and form interactions with key residues. Further experiments revealed that canagliflozin could effectively inhibit the migration and epithelial-mesenchymal-transition (EMT) of gastric cancer cells in vitro and in vivo. These results reveal a novel finding that canagliflozin has the potential to be an effective agent in inhibiting gastric cancer metastasis.

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“…Another study illustrated the mechanism of IL-6-induced EMT from an epigenetic standpoint. The authors found that exposing human peritoneal mesothelial cells to IL-6 increased the expression of histone deacetylase 6, which not only regulated IL-6 downstream of JAK2/STAT3 signaling but also activated TGF-β/Smad3 signaling, resulting in a change in the phenotype and increased cell migration 65 .…”

Section: The Role Of Il-6 In Fibrosis In Various Tissuesmentioning

confidence: 99%

The Role of IL-6 in Fibrotic Diseases: Molecular and Cellular Mechanisms

Li¹,

Zhao²,

Yuan³

et al. 2022

Int. J. Biol. Sci.

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Fibrosis is a detrimental outcome of most chronic inflammatory disorders and is defined by the buildup of excess extracellular matrix (ECM) components, which eventually leads to organ failure and death. Interleukin 6 (IL-6) is promptly produced by immune cells in response to tissue injuries and has a wide range of effects on cellular processes such as acute responses, hematopoiesis, and immune reactions. Furthermore, high levels of IL-6 have been found in a variety of chronic inflammatory disorders characterized by fibrosis, and this factor plays a significant role in fibrosis in various organs via Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) activation. Here, we review what is known about the role of IL-6 in fibrosis and why targeting IL-6 for fibrotic disease treatment makes sense.

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Requirement of Histone Deacetylase 6 for Interleukin-6 Induced Epithelial-Mesenchymal Transition, Proliferation, and Migration of Peritoneal Mesothelial Cells

Cited by 15 publications

References 39 publications

Pharmacologic Inhibition of Histone Deacetylase 6 Prevents the Progression of Chlorhexidine Gluconate-Induced Peritoneal Fibrosis by Blockade of M2 Macrophage Polarization

Pharmacologic Inhibition of Histone Deacetylase 6 Prevents the Progression of Chlorhexidine Gluconate-Induced Peritoneal Fibrosis by Blockade of M2 Macrophage Polarization

Canagliflozin, characterized as a HDAC6 inhibitor, inhibits gastric cancer metastasis

The Role of IL-6 in Fibrotic Diseases: Molecular and Cellular Mechanisms

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