Journal
MOLECULES AND CELLS
Volume 44, Issue 1, Pages 38-49Publisher
KOREAN SOC MOLECULAR & CELLULAR BIOLOGY
DOI: 10.14348/molcells.2020.0188
Keywords
HDAC2; MUC5AC; NF-kappa B; Smad3; transforming growth factor beta
Categories
Funding
- KRIBB Research Initiative Program - Ministry of Science ICT (MSIT)
- R&D Convergence Program of the National Research Council of Science and Technology [CAP-18-02KRIBB]
- National Research Foundation of Republic of Korea [NRF-2020R1A2C2006664, NRF2020R1C1C1011146]
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TGF beta activates Smad3/HDAC2 complex as a negative regulator for MUC5AC expression and mediates deacetylation of NF-kappa B at K310, reducing NF-kappa B transcriptional activity. Modulation of the TGF beta 1/Smad3/HDAC2/NF-kappa B pathway axis may be a promising approach to improve lung function in asthma and COPD.
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 beta (TGF beta) signaling pathway negatively regulates MUC5AC expression; however, the underlying molecular mechanism is not fully understood. Here, we showed that TGF beta 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 TGF beta receptor inhibitor (SB431542), but not by the inhibition of NF-kappa B (BAY11-7082 or Triptolide) or PI3K (LY294002) activities. TGF beta-activated Smad3 dose-dependently bound to MUC5AC promoter. Notably, TGF beta-activated Smad3 recruited HDAC2 and facilitated nuclear translocation of HDAC2, thereby inducing the deacetylation of NF-kappa B at K310, which is essential for a reduction in NF-kappa B transcriptional activity. Both TGF beta-induced nuclear translocation of Smad3/HDAC2 and deacetylation of NF-kappa B at K310 were suppressed by a Smad3 inhibitor (SIS3). These results suggest that the TGF beta-activated Smad3/HDAC2 complex is an essential negative regulator for MUC5AC expression and an epigenetic regulator for NF-kappa B acetylation. Therefore, these results collectively suggest that modulation of the TGF beta 1/Smad3/HDAC2/NF-kappa B pathway axis can be a promising way to improve lung function as a treatment strategy for asthma and COPD.
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