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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 STAT3(Lys685) acetylation with increased nuclear export of STAT3 to the cytoplasm. HDAC inhibition abolished STAT3(Tyr705) phosphorylation with minimal effect on STAT3(Ser727) and JAK2 tyrosine activity. pSTAT3(Tyr705)-positive DLBCLs were more sensitive to HDAC inhibition with LBH589 compared with pSTAT3(Tyr705)-negative DLBCLs. This cytotoxicity was associated with downregulation of the direct STAT3 target Mcl-1. HDAC3 knockdown upregulated STAT3(Lys685) acetylation but prevented STAT3(Tyr705) phosphorylation and inhibited survival of pSTAT3-positive DLBCL cells. These studies provide the rationale for targeting STAT3-positive DLBCL tumors with HDAC inhibitors.

Pubmed ID: 22116549


  • Gupta M
  • Han JJ
  • Stenson M
  • Wellik L
  • Witzig TE



Publication Data

June 6, 2012

Associated Grants

  • Agency: NCI NIH HHS, Id: P50 CA097274
  • Agency: NCI NIH HHS, Id: P50 CA097274
  • Agency: NCI NIH HHS, Id: R01 CA127433
  • Agency: NCI NIH HHS, Id: R01CA127433

Mesh Terms

  • Acetylation
  • Blotting, Western
  • Cell Nucleus
  • Cell Proliferation
  • Cytoplasm
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases
  • Humans
  • Hydroxamic Acids
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Indoles
  • Lymphoma, Large B-Cell, Diffuse
  • Phosphorylation
  • STAT3 Transcription Factor
  • Signal Transduction
  • Tumor Cells, Cultured
  • Tyrosine