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

Leukemia | Jun 6, 2012

http://www.ncbi.nlm.nih.gov/pubmed/22116549

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 RIS Download

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

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