title: Regulation of STAT3 by histone deacetylase-3 in diffuse large B-cell lymphoma: implications for therapy.
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 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.
authors: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA. Gupta.mamta@mayo.edu
authors: M
authors: M
authors: Gupta
authors: J J
authors: JJ
authors: Han
authors: M
authors: M
authors: Stenson
authors: L
authors: L
authors: Wellik
authors: T E
authors: TE
authors: Witzig
mesh_terms: D000107:Acetylation; D015153:Blotting, Western; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007211:Indoles; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000077767:Panobinostat; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D050796:STAT3 Transcription Factor; D014443:Tyrosine; D000099186:Histone Deacetylase 3