Transforming growth factor β inhibits MUC5AC expression by Smad3/HDAC2 complex formation and NF-κB deacetylation at K310 in NCI-H292 cells

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Title
Transforming growth factor β inhibits MUC5AC expression by Smad3/HDAC2 complex formation and NF-κB deacetylation at K310 in NCI-H292 cells
Author(s)
Su Ui LeeMun-Ock Kim; Myung Ji Kang; Eun Sol Oh; H Ro; Ro-Woon Lee; Yu Na Song; Sunin Jung; Jae-Won LeeSoo Yun Lee; Taeyeol Bae; S T Hong; Tae-Don Kim
Bibliographic Citation
Molecules and Cells, vol. 44, no. 1, pp. 38-49
Publication Year
2021
Abstract
Airway mucus secretion is an essential innate immune response for host protection. However, overproduction and hypersecretion of mucus, mainly composed of the gel- forming MUC5AC protein, are significant risk factors for patients with asthma and chronic obstructive pulmonary disease (COPD). The transforming growth factor β (TGFβ) signaling pathway negatively regulates MUC5AC expression; however, the underlying molecular mechanism is not fully understood. Here, we showed that TGFβ significantly reduces the expression of MUC5AC mRNA and its protein in NCI-H292 cells, a human mucoepidermoid carcinoma cell line. This reduced MUC5AC expression was restored by a TGFβ receptor inhibitor (SB431542), but not by the inhibition of NF-κB (BAY11-7082 or Triptolide) or PI3K (LY294002) activities. TGFβ-activated Smad3 dose-dependently bound to MUC5AC promoter. Notably, TGFβ-activated Smad3 recruited HDAC2 and facilitated nuclear translocation of HDAC2, thereby inducing the deacetylation of NF-κB at K310, which is essential for a reduction in NF-κB transcriptional activity. Both TGFβ-induced nuclear translocation of Smad3/HDAC2 and deacetylation of NF-κB at K310 were suppressed by a Smad3 inhibitor (SIS3). These results suggest that the TGFβ-activated Smad3/HDAC2 complex is an essential negative regulator for MUC5AC expression and an epigenetic regulator for NF-κB acetylation. Therefore, these results collectively suggest that modulation of the TGFβ1/Smad3/HDAC2/NF-κB pathway axis can be a promising way to improve lung function as a treatment strategy for asthma and COPD.
Keyword
HDAC2MUC5ACNF-κBSmad3Transforming growth factor β
ISSN
1016-8478
Publisher
Korea Soc-Assoc-Inst
DOI
http://dx.doi.org/10.14348/molcells.2020.0188
Type
Article
Appears in Collections:
Ochang Branch Institute > Natural Product Research Center > 1. Journal Articles
Division of Biomedical Research > Immunotherapy Research Center > 1. Journal Articles
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