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.