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Regulation of histone deacetylase 8 degradation by cAMP signaling system in lung cancer cells

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의과대학 의과학과
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서울대학교 대학원
AktapoptosisautophagycAMP signalingEpacHDAC8JNKlung cancerubiquitin-proteasome system
학위논문 (박사)-- 서울대학교 대학원 : 의과학과, 2017. 2. 전용성.
Histone deacetyalses (HDACs) are enzymes that remove acetyl groups from histones and other proteins and involved in epigenetic regulation of gene expression. Cyclic AMP (cAMP) signaling system is activated by cAMP formed by adenylate cyclases and regulates various cellular functions including gene expression, proliferation and apoptosis. However, the effect of the cAMP signaling system on HDACs has not been studied extensively. This study investigated how the cAMP signaling system regulates HDAC8 expression and its effects on apoptosis in human non-small cell lung cancer (NSCLC) cells.
Activation of cAMP signaling by isoproterenol or prostaglandin E2 (PGE2) increased the HDAC8 expression. Treatment with the exchange protein activated by cAMP (Epac)-selective 8-pCPT-cAMP increased the HDAC8 expression. Inhibition of Epac2 blocked the isoproterenol-induced HDAC8 expression, but the inhibition of PKA or Epac1 did not block the isoproterenol effect. Isoproterenol and 8-pCPT-cAMP activated Rap1, and Rap1A activation increased HDAC8 expression. Moreover, inhibition of Rap1A abolished the isoproterenol-induced increase in HDAC8 expression. Isoproterenol inhibited Akt by activation of Rap1A, and inhibition of PI3K/Akt activity led to a decrease in the MKK4/JNK pathway and an increase in HDAC8 expression. Activation of cAMP signaling increased HDAC8 protein expression without an increase in HDAC8 mRNA. Inhibition of proteasomal or lysosomal degradation abolished the increase in HDAC8 expression induced by isoproterenol or an Akt inhibitor. Activation of cAMP signaling inhibited autophagy and the ubiquitin-proteasome system and blocked HDAC8 degradation. cAMP signaling decreased the phosphorylation of Bcl-2, and Itch by inhibiting JNK activation, thereby reducing autophagy and the ubiquitin-proteasome system. Isoproterenol augmented cisplatin-induced apoptosis by increasing HDAC8 expression. Exogenous HDAC8 expression reduced the cisplatin-induced TIPRL expression, and knockdown of TIPRL expression augmented the cisplatin-induced apoptosis. The knockdown of HDAC8 restored the cisplatin-induced TIPRL expression and abolished the isoproterenol-induced augmentation of apoptosis. Isoproterenol repressed TIPRL gene transcription by increasing HDAC8 expression. In conclusion, the cAMP signaling system increases HDAC8 expression by inhibiting protein degradation through Epac2-Rap1A-mediated inhibition of PI3K/Akt-JNK pathways and thereby augments cisplatin-induced apoptosis via HDAC8-dependent repression of TIPRL expression in non-small cell lung cancer cells.
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