• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

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

Authors

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

Journal

Leukemia

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