title: cAMP signaling increases histone deacetylase 8 expression via the Epac2-Rap1A-Akt pathway in H1299 lung cancer cells.
abstract: This study was performed to investigate the signaling pathway that mediates cyclic AMP (cAMP)-induced inhibition of histone deacetylase 8 (HDAC8) degradation, and the effect and underlying mechanisms of the resulting increase in HDAC8 expression on cisplatin-induced apoptosis in lung cancer cells. cAMP signaling increased HDAC8 expression via a protein kinase A (PKA)-independent pathway in H1299 non-small cell lung cancer cells. However, treatment with a selective activator of an exchange protein that was activated by cAMP (Epac) increased HDAC8 expression, and Epac2 inhibition abolished the isoproterenol (ISO)-induced increase in HDAC8 expression. ISO and the Epac activator activated Rap1, and Rap1A activation increased HDAC8 expression; moreover, inhibition of Rap1A with a dominant negative Rap1A or by shRNA-mediated knockdown abolished the ISO-induced increase in HDAC8 expression. Activation of cAMP signaling and Rap1A decreased the activating phosphorylation of Akt. Akt inhibition with a pharmacological inhibitor or expression of a dominant negative Akt inhibited the MKK4/JNK pathway and increased HDAC8 expression. The Akt inhibitor-induced increase in HDAC8 expression was abolished by pretreatment with proteasomal or lysosomal inhibitors. The ISO treatment increased cisplatin-induced apoptosis, which was abolished by HDAC8 knockdown. Exogenous HDAC8 expression increased cisplatin-induced apoptosis and decreased TIPRL expression, and the knockdown of TIPRL increased the apoptosis of cisplatin-treated cells. The ISO treatment decreased cisplatin-induced transcription of the TIPRL gene in a HDAC8-dependent manner. In conclusion, the Epac-Rap1-Akt pathway mediates cAMP signaling-induced inhibition of JNK-dependent HDAC8 degradation, and the resulting HDAC8 increase augments cisplatin-induced apoptosis by repressing TIPRL expression in H1299 lung cancer cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.|Department of Biomedical Sciences and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.|Department of Biomedical Sciences and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yong-Sung
authors.initials: YS
authors.lastname: Juhnn
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C430803:RAP1A protein, human; C442864:RAPGEF4 protein, human; D012097:Repressor Proteins; D000242:Cyclic AMP; D051057:Proto-Oncogene Proteins c-akt; C409470:HDAC8 protein, human; D006655:Histone Deacetylases; D020827:rap1 GTP-Binding Proteins