This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Skov, S. Articles by Ødum, N. Search for Related Content PubMed PubMed Citation Articles by Skov, S. Articles by Ødum, N.

Cancer Cells Become Susceptible to Natural Killer Cell Killing after Exposure to Histone Deacetylase Inhibitors Due to Glycogen Synthase Kinase-3–Dependent Expression of MHC Class I–Related Chain A and B

¹ Institute of Molecular Biology and Physiology and Institute of Medical Microbiology and Immunology, University of Copenhagen; ² The Tumor Immunology Group, Danish Cancer Society, Copenhagen, Denmark; and ³ Department of Gastroenterology C-112, Herlev Hospital, Herlev, Denmark

Requests for reprints: Søren Skov, Institute of Medical Microbiology and Immunology, University of Copenhagen, Building 24-2-17, Blegdamsvej 3, 2200 Copenhagen N, Denmark. Phone: 45-35327679; E-mail: s.skov{at}immi.ku.dk.

We show that histone deacetylase (HDAC) inhibitors lead to functional expression of MHC class I–related chain A and B (MICA/B) on cancer cells, making them potent targets for natural killer (NK) cell–mediated killing through a NK group 2, member D (NKG2D) restricted mechanism. Blocking either apoptosis or oxidative stress caused by HDAC inhibitor treatment did not affect MICA/B expression, suggesting involvement of a separate signal pathway not directly coupled to induction of cell death. HDAC inhibitor treatment induced glycogen synthase kinase-3 (GSK-3) activity and down-regulation of GSK-3 by small interfering RNA or by different inhibitors showed that GSK-3 activity is essential for the induced MICA/B expression. We thus present evidence that cancer cells which survive the direct induction of cell death by HDAC inhibitors become targets for NKG2D-expressing cells like NK cells, T cells, and CD8 T cells.

This article has been cited by other articles:

				D. D. Vo, R. M. Prins, J. L. Begley, T. R. Donahue, L. F. Morris, K. W. Bruhn, P. de la Rocha, M.-Y. Yang, S. Mok, H. J. Garban, et al. Enhanced Antitumor Activity Induced by Adoptive T-Cell Transfer and Adjunctive Use of the Histone Deacetylase Inhibitor LAQ824 Cancer Res., November 15, 2009; 69(22): 8693 - 8699. [Abstract] [Full Text] [PDF]

				H. Jensen, L. Andresen, K. A. Hansen, and S. Skov Cell-surface expression of Hsp70 on hematopoietic cancer cells after inhibition of HDAC activity J. Leukoc. Biol., October 1, 2009; 86(4): 923 - 932. [Abstract] [Full Text] [PDF]

				M. C. Crisanti, A. F. Wallace, V. Kapoor, F. Vandermeers, M. L. Dowling, L. P. Pereira, K. Coleman, B. G. Campling, Z. G. Fridlender, G. D. Kao, et al. The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer Mol. Cancer Ther., August 1, 2009; 8(8): 2221 - 2231. [Abstract] [Full Text] [PDF]

				L. Andresen, K. A. Hansen, H. Jensen, S. F. Pedersen, P. Stougaard, H. R. Hansen, J. Jurlander, and S. Skov Propionic Acid Secreted from Propionibacteria Induces NKG2D Ligand Expression on Human-Activated T Lymphocytes and Cancer Cells J. Immunol., July 15, 2009; 183(2): 897 - 906. [Abstract] [Full Text] [PDF]

				M. Vales-Gomez, S. E. Chisholm, R. L. Cassady-Cain, P. Roda-Navarro, and H. T. Reyburn Selective Induction of Expression of a Ligand for the NKG2D Receptor by Proteasome Inhibitors Cancer Res., March 1, 2008; 68(5): 1546 - 1554. [Abstract] [Full Text] [PDF]

				S. Diermayr, H. Himmelreich, B. Durovic, A. Mathys-Schneeberger, U. Siegler, U. Langenkamp, J. Hofsteenge, A. Gratwohl, A. Tichelli, M. Paluszewska, et al. NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities Blood, February 1, 2008; 111(3): 1428 - 1436. [Abstract] [Full Text] [PDF]

				L. Andresen, H. Jensen, M. T. Pedersen, K. A. Hansen, and S. Skov Molecular Regulation of MHC Class I Chain-Related Protein A Expression after HDAC-Inhibitor Treatment of Jurkat T Cells J. Immunol., December 15, 2007; 179(12): 8235 - 8242. [Abstract] [Full Text] [PDF]

				L. Elsner, V. Muppala, M. Gehrmann, J. Lozano, D. Malzahn, H. Bickeboller, E. Brunner, M. Zientkowska, T. Herrmann, L. Walter, et al. The Heat Shock Protein HSP70 Promotes Mouse NK Cell Activity against Tumors That Express Inducible NKG2D Ligands J. Immunol., October 15, 2007; 179(8): 5523 - 5533. [Abstract] [Full Text] [PDF]

				A. Woetmann, P. Lovato, K. W. Eriksen, T. Krejsgaard, T. Labuda, Q. Zhang, A.-M. Mathiesen, C. Geisler, A. Svejgaard, M. A. Wasik, et al. Nonmalignant T cells stimulate growth of T-cell lymphoma cells in the presence of bacterial toxins Blood, April 15, 2007; 109(8): 3325 - 3332. [Abstract] [Full Text] [PDF]

				A. Lundqvist, S. I. Abrams, D. S. Schrump, G. Alvarez, D. Suffredini, M. Berg, and R. Childs Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: a novel method to potentiate natural killer cell tumor cytotoxicity. Cancer Res., July 15, 2006; 66(14): 7317 - 7325. [Abstract] [Full Text] [PDF]