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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
- Advisor
- 전용성
- Major
- 의과대학 협동과정 종양생물학전공
- Issue Date
- 2016-02
- Publisher
- 서울대학교 대학원
- Keywords
- cAMP ; cell migration ; histone deacetylase 6 ; isoproterenol ; lung cancer ; stress
- 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
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