Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation.
NF-kappaB activation is reciprocally regulated by RelA/p65 acetylation and deacetylation, which are mediated by histone acetyltransferases (HATs) and deacetylases (HDACs). Here we demonstrate that in leukemia cells, NF-kappaB activation by the HDAC inhibitors (HDACIs) MS-275 and suberoylanilide hydroxamic acid was associated with hyperacetylation and nuclear translocation of RelA/p65. The latter events, as well as the association of RelA/p65 with IkappaBalpha, were strikingly diminished by either coadministration of the IkappaBalpha phosphorylation inhibitor Bay 11-7082 (Bay) or transfection with an IkappaBalpha superrepressor. Inhibition of NF-kappaB by pharmacological inhibitors or genetic strategies markedly potentiated apoptosis induced by HDACIs, and this was accompanied by enhanced reactive oxygen species (ROS) generation, downregulation of Mn-superoxide dismutase and XIAP, and c-Jun N-terminal kinase 1 (JNK1) activation. Conversely, N-acetyl L-cysteine blocked apoptosis induced by Bay/HDACIs by abrogating ROS generation. Inhibition of JNK1 activation attenuated Bay/HDACI lethality without affecting NF-kappaB inactivation and ROS generation. Finally, XIAP overexpression dramatically protected cells against the Bay/HDACI regimen but failed to prevent ROS production and JNK1 activation. Together, these data suggest that HDACIs promote the accumulation of acetylated RelA/p65 in the nucleus, leading to NF-kappaB activation. Moreover, interference with these events by either pharmacological or genetic means leads to a dramatic increase in HDACI-mediated lethality through enhanced oxidative damage, downregulation of NF-kappaB-dependent antiapoptotic proteins, and stress-related JNK1 activation.
Dai
Yun
Y
Department of Medicine, Virginia Commonwealth University/Massey Cancer Center, Richmond, Virginia 23298, USA.
Rahmani
Mohamed
M
Dent
Paul
P
Grant
Steven
S
D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology; D015536:Down-Regulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019169:Jurkat Cells; D007938:Leukemia / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress; D011506:Proteins / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D051996:Transcription Factor RelA; D020298:U937 Cells; D000077337:Vorinostat; D051636:X-Linked Inhibitor of Apoptosis Protein
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; D009570:Nitriles; D011506:Proteins; D011725:Pyridines; D017382:Reactive Oxygen Species; D013450:Sulfones; D051996:Transcription Factor RelA; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C118739:entinostat; D000077337:Vorinostat; D013482:Superoxide Dismutase; D048031:JNK Mitogen-Activated Protein Kinases