title: Isoproterenol increases histone deacetylase 6 expression and cell migration by inhibiting ERK signaling via PKA and Epac pathways in human lung cancer cells.
abstract: Stress conditions are correlated with tumor growth, progression and metastasis. We hypothesized that stress signals might affect tumor progression via epigenetic control of gene expression and investigated the effects of stress signals on the expression levels of histone deacetylases (HDACs) and the underlying mechanisms of these effects in lung cancer cells. Treatment with isoproterenol (ISO), an analog of the stress signal epinephrine, increased the expression of HDAC6 protein and mRNA in H1299 lung cancer cells. ISO caused the deacetylation of α-tubulin and stimulated cell migration in an HDAC6-dependent manner. HDAC6 expression was increased by treatment with selective activators of cAMP-dependent protein kinase (PKA) or exchange protein activated by cAMP (Epac). ISO activated Rap1 via Epac, and constitutively active Rap1A increased the HDAC6 level; however, the knockdown of Rap1A decreased the 8-(4-cholorophenylthio)-2'-O-methyl-cAMP-induced increase in HDAC6 expression. Both PKA and Rap1A decreased c-Raf activation to inhibit extracellular signal-regulated kinase (ERK) signaling. Inhibition of ERK caused an increase in HDAC6 expression, and constitutively active MEK1 decreased the ISO-induced HDAC6 expression. We concluded that ISO increases HDAC6 expression via a PKA/Epac/ERK-dependent pathway that stimulates the migration of lung cancer cells. This study suggests that stress signals can stimulate the migration of cancer cells by inducing HDAC6 expression in lung cancer cells.
authors.affiliation: Department of Biochemistry and Molecular Biology and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jeong Ah
authors.initials: JA
authors.lastname: Lim
authors.affiliation: Department of Biochemistry and Molecular Biology and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yong-Sung
authors.initials: YS
authors.lastname: Juhnn
mesh_terms: D000072283:A549 Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004837:Epinephrine / Q000031:analogs & derivatives; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D000073864:Histone Deacetylase 6 / Q000235:genetics*; D006801:Humans; D007545:Isoproterenol / Q000009:adverse effects; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological; D013566:Sympathomimetics / Q000009:adverse effects
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; D013566:Sympathomimetics; D017868:Cyclic AMP-Dependent Protein Kinases; D000073864:Histone Deacetylase 6; D007545:Isoproterenol; D004837:Epinephrine