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Molecular mechanism for cAMP signaling to regulate HDAC6 expression in non-small cell lung cancer
cAMP 신호전달계가 폐암 세포주에서 HDAC6의 발현을 조절하는 분자기전

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Authors
임정아
Advisor
전용성
Major
의과대학 협동과정 종양생물학전공
Issue Date
2016-02
Publisher
서울대학교 대학원
Keywords
cAMPcell migrationhistone deacetylase 6isoproterenollung cancerstress
Description
학위논문 (박사)-- 서울대학교 대학원 : 의과대학협동과정 종양생물학전공, 2016. 2. 전용성.
Abstract
Stress conditions are correlated with tumor growth, progression and metastasis. Epinephrine signaling is activated during stress conditions. Isoproterenol, an epinephrine analog, binds and activates -adrenergic receptor to stimulate cAMP production and regulate various cellular metabolism and gene expression. -Tubulin is deacetylated by histone deacetylase 6 (HDAC6), which affects the microtubule dynamics to regulate cell migration. This study investigated the mechanism for stress signals to modulate the migration of non-small cell lung cancer cells via regulation of HDAC6 expression. Treatment of H1299 lung cancer cells with isoproterenol decreased the acetylation level of -tubulin and stimulated cell migration. Isoproterenol treatment also increased the expression of HDAC6. Isoproterenol-stimulated cell migration was blocked by knockdown of HDAC6. Treatment with N6-phenyl-cAMP, a selective activator of protein kinase A (PKA), and 8-pCPT-2’-O-Me-cAMP (8-pCPT), a selective activator of exchange protein activated by cAMP (Epac), increased HDAC6 expression. Isoproterenol and 8-pCPT increased Rap1 activity, which acts downstream of Epac. Constitutively active Rap1A increased HDAC6 expression and the knockdown of Rap1A decreased isoproterenol-induced HDAC6 expression. Isoproterenol inhibited External signal-activated kinase (ERK) in H1299 cells. Inhibition of ERK increased HDAC6 levels, and the expression of constitutively active MAPK kinase (MEK1) decreased isoproterenol-induced HDAC6 expression. It is concluded that isoproterenol increases HDAC6 expression via PKA/Epac/ERK-dependent pathway, and isoproterenol-induced HDAC6 expression increases the migration of lung cancer cells. This study suggests that stress signal can stimulate the migration of cancer cells by increasing the expression of HDAC6.
Language
English
URI
http://hdl.handle.net/10371/121778
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College of Medicine/School of Medicine (의과대학/대학원)Program in Cancer Biology (협동과정-종양생물학전공)Theses (Ph.D. / Sc.D._협동과정-종양생물학전공)
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