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M211695200v1
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Papers In Press, published online ahead of print March 20, 2003
J. Biol. Chem, 10.1074/jbc.M211695200
Submitted on November 18, 2002
Revised on March 17, 2003
Accepted on March 20, 2003

Ineffectiveness of HDAC inhibitors to induce apoptosis involves the transcriptional activation of NF-kappa B through the Akt pathway

Marty W. Mayo, Chadrick E. Denlinger, Robert M. Broad, Fan Yeung, Eugene T. Reilly, Yang Shi, and David R. Jones

Thoracic and Cardiovascular Surgery, University of Virginia, Charlottesville, VA 22908-0679

Corresponding Author: mwm3y{at}virginia.edu

Histone deacetylase (HDAC) inhibitors are emerging as a new class of anticancer agents for the treatment of solid and hematological malignancies. Although HDAC inhibitors induce cell death through an apoptotic process, little is known about the molecular events that control their effectiveness. In this study, we demonstrate that HDAC inhibitors are limited in their ability to induce apoptosis in non-small cell lung cancer (NSCLC) cell lines despite their ability to effectively inhibit deacetylase activity. Since the anti-apoptotic transcription factor NF-kB has been shown to be under the control of HDAC-mediated repression, we analyzed whether HDAC-inhibitors activated NF-kB in NSCLC cells. HDAC inhibitors effectively stimulated endogenous NF-kB-dependent gene expression by upregulating IL-8, Bcl-XL, and MMP-9 transcripts. The ability of HDAC inhibitors to increase NF-kB transcriptional activity was not associated with signaling events that stimulated nuclear translocation, but rather modulated the transactivation potential of the RelA/p65 subunit of NF-kB in an Akt-dependent manner. Moreover, Akt directly phosphorylated the co-activator protein p300 and was required for loading and activation of transcriptional co-activaotrs. Selective inhibition of either the PI3K/Akt pathway or NF-kB itself blocked the ability of HDAC inhibitors to activate NF-kB and dramatically sensitized NSCLC cells to apoptosis following of the addition of HDAC inhibitors. Our study indicates that the ineffectiveness of HDAC inhibitors to induce apoptosis in NSCLC cancer cells is associated with the ability of these molecules to stimulate NF-kB-dependent transcription and cell survival.


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