Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-κB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-jun n-terminal kinase 1 activation

NF-kappa B activation is reciprocally regulated by ReIA/p65 acetylation and deacetylation, which are mediated by histone acetyltransferases (HATs) and deacetylases (HDACs). Here we demonstrate that in leukemia cells, NF-kappa B activation by the HDAC inhibitors (HDACIs) MS-275 and suberoylanilide hydroxamic acid was associated with hyperacetylation and nuclear translocation of ReIA/p65. The latter events, as well as the association of RelA/p65 with I kappa B alpha, were strikingly diminished by either coadministration of the I kappa B alpha phosphorylation inhibitor Bay 11-7082 (Bay) or transfection with an I kappa B alpha superrepressor. Inhibition of NF-kappa B 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-Jum 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-kappa B inactivation and ROS generation. Finally, XIAP overexpression dramatically protected cells against the Bay/HDACI regimen but failed to prevent ROS production and JNKI activation. Together, these data suggest that HDACIs promote the accumulation of acetylated ReIA/p65 in the nucleus, leading to NF-kappa B 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-kappa B-dependent antiapoptotic proteins, and stress-related JNK1 activation.