RRC ID 65826
Author Hichino A, Okamoto M, Taga S, Akizuki R, Endo S, Matsunaga T, Ikari A.
Title Down-regulation of Claudin-2 Expression and Proliferation by Epigenetic Inhibitors in Human Lung Adenocarcinoma A549 Cells.
Journal J Biol Chem
Abstract Claudin-2 is highly expressed in lung adenocarcinoma tissues and increases proliferation in adenocarcinoma cells. The chemicals that reduce claudin-2 expression may have anti-cancer effects, but such therapeutic medicines have not been developed. We found that azacitidine (AZA), a DNA methylation inhibitor, and trichostatin A (TSA) and sodium butyrate (NaB), histone deacetylase (HDAC) inhibitors, decrease claudin-2 levels. The effect of AZA was mediated by the inhibition of phosphorylated Akt and NF-κB. LY-294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), and BAY 11-7082, an NF-κB inhibitor, decreased claudin-2 levels. The reporter activity of claudin-2 was decreased by AZA and LY-294002, which was blocked by the mutation in a putative NF-κB-binding site. NF-κB bound to the promoter region of claudin-2, which was inhibited by AZA and LY-294002. AZA is suggested to decrease the claudin-2 mRNA level mediated by the inhibition of a PI3K/Akt/NF-κB pathway. TSA and NaB did not change phosphorylated Akt and NF-κB levels. Furthermore, these inhibitors did not change the reporter activity of claudin-2 but decreased the stability of claudin-2 mRNA mediated by the elevation of miR-497 microRNA. The binding of histone H3 to the promoter region of miR-497 was inhibited by TSA and NaB, whereas that of claudin-2 was not. These results suggest that HDAC inhibitors decrease claudin-2 levels mediated by the elevation of miR-497 expression. Cell proliferation was additively decreased by AZA, TSA, and NaB, which was partially rescued by ectopic expression of claudin-2. We suggest that epigenetic inhibitors suppress the abnormal proliferation of lung adenocarcinoma cells highly expressing claudin-2.
Volume 292(6)
Pages 2411-2421
Published 2017-2-10
DOI 10.1074/jbc.M116.762807
PII S0021-9258(20)42496-2
PMID 28057758
PMC PMC5313110
MeSH A549 Cells Adenocarcinoma / genetics Adenocarcinoma / metabolism* Adenocarcinoma / pathology Adenocarcinoma of Lung Azacitidine / pharmacology Butyric Acid / pharmacology Cell Proliferation / drug effects* Chromones / pharmacology Claudin-2 / genetics Claudin-2 / metabolism* Down-Regulation* Epigenesis, Genetic / drug effects* Humans Hydroxamic Acids / pharmacology Lung Neoplasms / genetics Lung Neoplasms / metabolism* Lung Neoplasms / pathology MicroRNAs / metabolism Morpholines / pharmacology Nitriles / pharmacology RNA, Messenger / genetics Signal Transduction / drug effects Sulfones / pharmacology
IF 4.238
Human and Animal Cells A549