Isoproterenol increases histone deacetylase 6 expression and cell migration by inhibiting ERK signaling via PKA and Epac pathways in human lung cancer cells

• Published in: Experimental & molecular medicine 2016-01, Vol.48 (1), p.e204-e204
• Main Authors: Lim, Jeong Ah, Juhnn, Yong-Sung
• Format: Article
• Language: English
• Subjects: 13/2; 13/95; 45/29; 692/163; 692/308/575; 96/106; 96/109; A549 Cells; Biomedical and Life Sciences; Biomedicine; Cell Line, Tumor; Cell Movement - drug effects; Cyclic AMP-Dependent Protein Kinases - metabolism; Epinephrine - analogs & derivatives; Gene Expression Regulation, Neoplastic - drug effects; Guanine Nucleotide Exchange Factors - metabolism; Histone Deacetylase 6 - genetics; Humans; Isoproterenol - adverse effects; Lung Neoplasms - etiology; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; MAP Kinase Signaling System - drug effects; Medical Biochemistry; Molecular Medicine; Original; original-article; Signal Transduction - drug effects; Stem Cells; Stress, Physiological; Sympathomimetics - adverse effects
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/emm.2015.98

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. Cancer: Stress promotes cell migration Stress signals promote the proliferation and migration of lung cancer cells via mechanisms that modify gene expression. Jeong Ah Lim and Yong-Sung Juhnn from Seoul National University College of Medicine in South Korea treated cell lines derived from human non-small cell lung tumors with a chemical called isoproterenol, an analog of the stress hormone epinephrine. They observed an increase in histone acetylase 6, an enzyme that controls gene expression through removal of chemical tags on chromosome packaging molecules called histones and other non-histone proteins. Through a series of molecular steps, the cancer cells then gain the ability to disseminate and metastasize. Drugs that block histone deacetylases are now under development for treating cancer. The new findings suggest that these agents may work in part by blocking stress responses in tumors.