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Lymphoma

Regulation of STAT3 by histone deacetylase-3 in diffuse large B-cell lymphoma: implications for therapy

Leukemia volume 26, pages 1356–1364 (2012)Cite this article

Abstract

Diffuse large B-cell lymphoma (DLBCL) with an activated B-cell (ABC) gene-expression profile has been shown to have a poorer prognosis compared with tumors with a germinal center B-cell type. ABC cell lines have constitutive activation of STAT3; however, the mechanisms regulating STAT3 signaling in lymphoma are unknown. In studies of class-I histone deacetylase (HDAC) expression, we found overexpression of HDAC3 in phospho STAT3-positive DLBCL and the HDAC3 was found to be complexed with STAT3. Inhibition of HDAC activity by panobinostat (LBH589) increased p300-mediated STAT3Lys685 acetylation with increased nuclear export of STAT3 to the cytoplasm. HDAC inhibition abolished STAT3Tyr705 phosphorylation with minimal effect on STAT3Ser727 and JAK2 tyrosine activity. pSTAT3Tyr705-positive DLBCLs were more sensitive to HDAC inhibition with LBH589 compared with pSTAT3Tyr705-negative DLBCLs. This cytotoxicity was associated with downregulation of the direct STAT3 target Mcl-1. HDAC3 knockdown upregulated STAT3Lys685 acetylation but prevented STAT3Tyr705 phosphorylation and inhibited survival of pSTAT3-positive DLBCL cells. These studies provide the rationale for targeting STAT3-positive DLBCL tumors with HDAC inhibitors.

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Acknowledgements

This work is supported by Lymphoma SPORE (P50 CA097274) Career Development Award to MG (from NCI/ University of Iowa/Mayo Clinic); R01CA127433 to TEW and the Predolin Foundation.

Author contributions

MG and TEW designed the research. MG interpreted and analyzed all the data, made the figures and wrote the manuscript. MG, MJS, JJH and LEW performed the experiments. TEW provided clinical samples and wrote the manuscript.

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  1. M Gupta and T E Witzig: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    M Gupta, J J Han, M Stenson, L Wellik & T E Witzig

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  1. M Gupta
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  2. J J Han
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Correspondence to M Gupta or T E Witzig.

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Gupta, M., Han, J., Stenson, M. et al. Regulation of STAT3 by histone deacetylase-3 in diffuse large B-cell lymphoma: implications for therapy. Leukemia 26, 1356–1364 (2012). https://doi.org/10.1038/leu.2011.340

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