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J. Biol. Chem., Vol. 283, Issue 24, 16818-16829, June 13, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/24/16818    most recent M710177200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Ishdorj, G. Articles by Gibson, S. B. PubMed PubMed Citation Articles by Ishdorj, G. Articles by Gibson, S. B. Social Bookmarking                      What's this?

Lysophosphatidic Acid Protects Cancer Cells from Histone Deacetylase (HDAC) Inhibitor-induced Apoptosis through Activation of HDAC^*

Ganchimeg Ishdorj, Bonnie A. Graham, Xiaojie Hu, Jing Chen^¶, James B. Johnston^||, Xianjun Fang^¶, and Spencer B. Gibson¹

From the Manitoba Institute of Cell Biology, Winnipeg, Manitoba R3E 0V9, Canada, the Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba R3E 0V9, Canada, the ^||Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0V9, Canada, and the ^¶Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298

Histone deacetylases (HDACs) catalyze the removal of acetyl groups from histones and contribute to transcriptional repression. In addition, the HDAC inhibitors induce apoptosis in cancer cells through alterations in histone acetylation and activation of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) apoptotic pathway. Lysophosphatidic acid (LPA) is a growth factor that promotes survival of cancer cells through activation of G protein-coupled receptors. Here we show that HDAC inhibitors can induce apoptosis through activation of the TRAIL apoptotic pathway, and LPA prevented HDAC inhibitor-induced apoptosis and increased TRAIL receptor DR4 (death receptor 4) protein expression. This was associated with increased HDAC1 recruitment to the DR4 promoter following LPA treatment and a reduction in HDAC inhibitor-induced histone acetylation in the DR4 promoter. In addition, LPA induces HDAC enzyme activity in a dose- and time-dependent manner, and this is associated with HDAC1 activation and increased binding of HDAC1 to HDAC2. Reducing the expression of HDAC1 significantly lowered LPA-induced HDAC activity and increased histone acetylation. LPA induction of HDAC activity was blocked by the LPA receptor antagonist, Ki16425, or by inhibiting receptor activation with pertussis toxin. Reducing the expression of the LPA receptor LPA₁ also blocked LPA-induced HDAC activation. In addition, LPA reduced histone acetyltransferase enzymatic activity. Finally, LPA attenuated the ability of the HDAC inhibitor to reduce HDAC activity. Thus, LPA enhances survival of cancer cells by increasing HDAC activity and reducing histone acetylation.

Received for publication, December 13, 2007 , and in revised form, April 10, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant CA 102196 (to X. F.). This work was also supported by a translational research grant from the Leukemia and Lymphoma Society and CancerCare Manitoba Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Manitoba Institute of Cell Biology, University of Manitoba, 675 McDermot Ave., Rm. ON5042, Winnipeg, Manitoba R3E 0V9, Canada. Tel./Fax: 204-787-2051/787-2190; E-mail: gibsonsb{at}cc.umanitoba.ca.

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