KMID : 0578320210440010038
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Molecules and Cells 2021 Volume.44 No. 1 p.38 ~ p.49
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Transforming Growth Factor ¥â Inhibits MUC5AC Expression by Smad3/HDAC2 Complex Formation and NF-¥êB Deacetylation at K310 in NCI-H292 Cells
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Lee Su-Ui
Kim Mun-Ock Kang Myung-Ji Oh Eun-Sol Ro Hyun-Ju Lee Ro-Woon Song Yu-Na Jung Sun-In Lee Jae-Won Lee Soo-Yun Bae Tae-Yeol Hong Sung-Tae Kim Tae-Don
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Abstract
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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 ¥â (TGF¥â) signaling pathway negatively regulates MUC5AC expression; however, the underlying molecular mechanism is not fully understood. Here, we showed that TGF¥â 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¥â receptor inhibitor (SB431542), but not by the inhibition of NF-¥êB (BAY11-7082 or Triptolide) or PI3K (LY294002) activities. TGF¥â-activated Smad3 dose-dependently bound to MUC5AC promoter. Notably, TGF¥â-activated Smad3 recruited HDAC2 and facilitated nuclear translocation of HDAC2, thereby inducing the deacetylation of NF-¥êB at K310, which is essential for a reduction in NF-¥êB transcriptional activity. Both TGF¥â-induced nuclear translocation of Smad3/HDAC2 and deacetylation of NF-¥êB at K310 were suppressed by a Smad3 inhibitor (SIS3). These results suggest that the TGF¥â-activated Smad3/HDAC2 complex is an essential negative regulator for MUC5AC expression and an epigenetic regulator for NF-¥êB acetylation. Therefore, these results collectively suggest that modulation of the TGF¥â1/Smad3/HDAC2/NF-¥êB pathway axis can be a promising way to improve lung function as a treatment strategy for asthma and COPD.
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KEYWORD
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HDAC2, MUC5AC, NF-¥êB, Smad3, transforming growth factor ¥â
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