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

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.

[1]  Wei-Guo Zhu,et al.  Acetylation of p53 at Lysine 373/382 by the Histone Deacetylase Inhibitor Depsipeptide Induces Expression of p21Waf1/Cip1 , 2006, Molecular and Cellular Biology.

[2]  M. Tremblay,et al.  Protein Tyrosine Phosphatases, TC-PTP, SHP1, and SHP2, Cooperate in Rapid Dephosphorylation of Stat3 in Keratinocytes Following UVB Irradiation , 2010, PLoS ONE.

[3]  Charles Giardina,et al.  HDAC3 overexpression and colon cancer cell proliferation and differentiation , 2008, Molecular carcinogenesis.

[4]  E. Verdin,et al.  NF‐κB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation , 2006, The EMBO journal.

[5]  G. Draetta,et al.  Role for Histone Deacetylase 1 in Human Tumor Cell Proliferation , 2007, Molecular and Cellular Biology.

[6]  L. Augenlicht,et al.  Requirement of Histone Deacetylase Activity for Signaling by STAT1* , 2004, Journal of Biological Chemistry.

[7]  A. V. van Kuilenburg,et al.  Histone deacetylases (HDACs): characterization of the classical HDAC family. , 2003, The Biochemical journal.

[8]  Y. E. Chin,et al.  Stat3 Dimerization Regulated by Reversible Acetylation of a Single Lysine Residue , 2005, Science.

[9]  Tony Kouzarides,et al.  Acetylation of importin-α nuclear import factors by CBP/p300 , 2000, Current Biology.

[10]  E. Seto,et al.  HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention , 2007, Oncogene.

[11]  Xiaomin Chen,et al.  Stat Acetylation--A Key Facet of Cytokine Signaling? , 2005, Science.

[12]  S. Bhattacharya,et al.  Regulation of Stat3 nuclear export. , 2003, The Journal of clinical investigation.

[13]  E. Vellenga,et al.  Ser727‐dependent transcriptional activation by association of p300 with STAT3 upon IL‐6 stimulation , 2001, FEBS letters.

[14]  L. Staudt,et al.  Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large B-cell lymphoma. , 2008, Blood.

[15]  M. P. Holloway,et al.  Acetylation Directs Survivin Nuclear Localization to Repress STAT3 Oncogenic Activity* , 2010, The Journal of Biological Chemistry.

[16]  Kai Fu,et al.  Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  S. Minucci,et al.  Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer , 2006, Nature Reviews Cancer.

[18]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[19]  K. Miyazono,et al.  Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. , 1999, Science.

[20]  R. Johnstone,et al.  Panobinostat (LBH589): a potent pan-deacetylase inhibitor with promising activity against hematologic and solid tumors. , 2009, Future oncology.

[21]  G. Cattoretti,et al.  Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. , 2007, Blood.

[22]  J. Turkson,et al.  Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. , 1999, Immunity.

[23]  Andrew J. Bannister,et al.  Acetylation of importin-alpha nuclear import factors by CBP/p300. , 2000, Current biology : CB.

[24]  N. L. La Thangue,et al.  Histone deacetylase inhibitors open new doors in cancer therapy. , 2004, Biochemical pharmacology.

[25]  厨子 慎一郎.  STAT3 mediates the survival signal in oncogenic ras-transfected intestinal epithelial cells , 1998 .

[26]  Jianyuan Luo,et al.  Activation of Stat3 Sequence-specific DNA Binding and Transcription by p300/CREB-binding Protein-mediated Acetylation* , 2005, Journal of Biological Chemistry.

[27]  M. Chiariello,et al.  Selective transcription and cellular proliferation induced by PDGF require histone deacetylase activity. , 2006, Biochemical and biophysical research communications.

[28]  L. Staudt,et al.  Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. , 2004, Blood.

[29]  R. Stauber,et al.  A phosphorylation-acetylation switch regulates STAT1 signaling. , 2009, Genes & development.

[30]  J. Darnell,et al.  Signalling: STATs: transcriptional control and biological impact , 2002, Nature Reviews Molecular Cell Biology.

[31]  Johnson M Liu,et al.  Chromatin remodeling and leukemia: new therapeutic paradigms. , 1999, Blood.

[32]  Shaji K. Kumar,et al.  Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. , 2009, Blood.

[33]  J. Darnell,et al.  Two contact regions between Stat1 and CBP/p300 in interferon γ signaling , 1996 .

[34]  Meland,et al.  The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. , 2002, The New England journal of medicine.

[35]  Adrian Wiestner,et al.  A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  K. Bhalla,et al.  A Phase I Study of Intravenous LBH589, a Novel Cinnamic Hydroxamic Acid Analogue Histone Deacetylase Inhibitor, in Patients with Refractory Hematologic Malignancies , 2006, Clinical Cancer Research.

[37]  G. Cattoretti,et al.  Constitutively activated STAT 3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas , 2008 .

[38]  J. Darnell,et al.  Two contact regions between Stat1 and CBP/p300 in interferon gamma signaling. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[39]  J. Darnell.  STATs and gene regulation. , 1997, Science.

[40]  Stuart L Schreiber,et al.  Deacetylase enzymes: biological functions and the use of small-molecule inhibitors. , 2002, Chemistry & biology.

[41]  A. Brasier,et al.  Requirement of histone deacetylase1 (HDAC1) in signal transducer and activator of transcription 3 (STAT3) nucleocytoplasmic distribution , 2008, Nucleic acids research.

[42]  D. Lavelle,et al.  Histone deacetylase inhibitors increase p21WAF1 and induce apoptosis of human myeloma cell lines independent of decreased IL‐6 receptor expression , 2001, American journal of hematology.

[43]  J. Qin,et al.  Both corepressor proteins SMRT and N‐CoR exist in large protein complexes containing HDAC3 , 2000, The EMBO journal.