Activation of NF-kappaB by HDAC inhibitor apicidin through Sp1-dependent de novo protein synthesis: its implication for resistance to apoptosis.
Histone deacetylase (HDAC) inhibitors are promising anti-cancer drugs, but these exert differential responses depending on the cell types. Here, we demonstrate a new mechanism for activation of nuclear factor-kappaB (NF-kappaB) by HDAC inhibitor apicidin and the role of NF-kappaB signaling pathway for mediating differential cellular responses, especially, apoptosis. Treatment of HeLa cells with apicidin increases transcriptional activity of NF-kappaB and its target gene IL-8 and cIAP-1 induction, which involves the activation of IKK-IkappaBalpha signaling pathway through Sp1-dependent de novo protein synthesis. In parallel, apicidin treatment leads to histone hyperacetylation in the IL-8 promoter region independent of NF-kappaB signaling pathway, which is not sufficient for full transcription of IL-8 gene. This NF-kappaB activation contributes to resistance of HeLa cells to apoptotic potential of apicidin. Collectively, our results suggest that activation of NF-kappaB signaling cascade functions as a critical modulator to determine cell fate on apoptosis in response to HDAC inhibitors.
Kim
Y K
YK
1College of Medicine, Kwandong University, Gangneung 210-701, Korea.
Lee
E K
EK
Kang
J K
JK
Kim
J A
JA
You
J-S
JS
Park
J H
JH
Seo
D-W
DW
Hwang
J W
JW
Kim
S-N
SN
Lee
H Y
HY
Lee
H W
HW
Han
J-W
JW
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000502:physiology*
D056572:Histone Deacetylase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D016209:Interleukin-8; D016328:NF-kappa B; D010456:Peptides, Cyclic; D016329:Sp1 Transcription Factor; C102351:apicidin; D051550:I-kappa B Kinase