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Molecular and Cellular Biology, July 2005, p. 5429-5444, Vol. 25, No. 13
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.13.5429-5444.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Blockade of Histone Deacetylase Inhibitor-Induced RelA/p65 Acetylation and NF-{kappa}B Activation Potentiates Apoptosis in Leukemia Cells through a Process Mediated by Oxidative Damage, XIAP Downregulation, and c-Jun N-Terminal Kinase 1 Activation

Yun Dai,1 Mohamed Rahmani,1 Paul Dent,3,4 and Steven Grant1,2,3*

Departments of Medicine,1 Biochemistry,2 Pharmacology,3 Radiation Oncology, Virginia Commonwealth University/Massey Cancer Center, Richmond, Virginia 232984

Received 23 November 2004/ Returned for modification 4 January 2005/ Accepted 29 March 2005

NF-{kappa}B 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-{kappa}B 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 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-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-{kappa}B 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-{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.

* Corresponding author. Mailing address: Division of Hematology/Oncology, Virginia Commonwealth University/Medical College of Virginia, MCV Station, Box 230, Richmond, VA 23298. Phone: (804) 828-5211. Fax: (804) 828-2174. E-mail: stgrant{at}hsc.vcu.edu.

Molecular and Cellular Biology, July 2005, p. 5429-5444, Vol. 25, No. 13
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.13.5429-5444.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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