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http://dx.doi.org/10.14348/molcells.2020.0188

Transforming Growth Factor β Inhibits MUC5AC Expression by Smad3/HDAC2 Complex Formation and NF-κB Deacetylation at K310 in NCI-H292 Cells  

Lee, Su Ui (Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))
Kim, Mun-Ock (Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))
Kang, Myung-Ji (Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))
Oh, Eun Sol (Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))
Ro, Hyunju (Department of Biological Sciences, College of Bioscience and Biotechnology, Chungnam National University)
Lee, Ro Woon (Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))
Song, Yu Na (Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))
Jung, Sunin (Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))
Lee, Jae-Won (Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))
Lee, Soo Yun (Immunotherapy Research Center, KRIBB)
Bae, Taeyeol (Immunotherapy Research Center, KRIBB)
Hong, Sung-Tae (Department of Anatomy & Cell Biology, Department of Medical Science, Chungnam National University College of Medicine)
Kim, Tae-Don (Immunotherapy Research Center, KRIBB)
Publication Information
Molecules and Cells / v.44, no.1, 2021 , pp. 38-49 More about this Journal
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.
Keywords
HDAC2; MUC5AC; NF-${\kappa}B$; Smad3; transforming growth factor ${\beta}$;
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