Suberoylanilide hydroxamic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing nuclear factor-κB activation

Because of its ability to suppress tumor cell proliferation, angiogenesis, and inflammation, the histone deacetylase inhibitor suberoylanilide hydroxamic acid ( SAHA) is currently in clinical trials. How SAHA mediates its effects is poorly understood. We found that in several human cancer cell lines, SAHA potentiated the apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents and inhibited TNF-induced invasion and receptor activator of NF-kappa B ligand-induced osteoclastogenesis, all of which are known to require NF-kappa B activation. These observations corresponded with the down-regulation of the expression of anti-apoptotic (IAP1, IAP2, X chromosome- linked IAP, Bcl-2, Bcl-x(L), TRAF1, FLIP, and survivin), proliferative ( cyclin D1, cyclooxygenase 2, and c-Myc), and angiogenic (ICAM-1, matrix metalloproteinase-9, and vascular endothelial growth factor) gene products. Because several of these genes are regulated by NF-kappa B, we postulated that SAHA mediates its effects by modulating NF-kappa B and found that SAHA suppressed NF-kappa B activation induced by TNF, IL-1 beta, okadaic acid, doxorubicin, lipopolysaccharide, H2O2, phorbol myristate acetate, and cigarette smoke; the suppression was not cell type-specific because both inducible and constitutive NF-kappa B activation was inhibited. We also found that SAHA had no effect on direct binding of NF-kappa B to the DNA but inhibited sequentially the TNF-induced activation of I kappa B alpha kinase, I kappa B alpha phosphorylation, I kappa B alpha ubiquitination, I kappa B alpha degradation, p65 phosphorylation, and p65 nuclear translocation. Furthermore, SAHA inhibited the NF-kappa B-dependent reporter gene expression activated by TNF, TNFR1, TRADD, TRAF2, NF-kappa B-inducing kinase, I kappa B alpha kinase, and the p65 subunit of NF-kappa B. Overall, our results indicated that NF-kappa B and NF-kappa B-regulated gene expression inhibited by SAHA can enhance apoptosis and inhibit invasion and osteoclastogenesis.