Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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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)
  • Received : 2020.09.15
  • Accepted : 2021.01.12
  • Published : 2021.01.31
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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

Acknowledgement

This work was supported by the KRIBB Research Initiative Program funded by the Ministry of Science ICT (MSIT), the R&D Convergence Program of the National Research Council of Science and Technology (CAP-18-02KRIBB), and the National Research Foundation (NRF-2020R1A2C2006664 and NRF2020R1C1C1011146) of Republic of Korea.

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