Gankyrin is an oncoprotein commonly overexpressed in hepatocellular carcinomas. It interacts with multiple proteins and accelerates degradation of tumor suppressors Rb and p53. Since gankyrin consists of 7 ankyrin repeats and is structurally similar to IkBs, we investigated its interaction with NF-KB. We found that gankyrin directly binds to RelA. In HeLa and 293 cells, overexpression of gankyrin suppressed the basal as well as TNF alpha-induced transcriptional activity of NF-KB, whereas down-regulation of gankyrin increased it. Gankyrin did not affect the NF-KB DNA-binding activity or nuclear translocation of RelA induced by TNF alpha in these cells. Leptomycin B that inhibits nuclear export of ReIA suppressed the NF-kB activity, which was further suppressed by gankyrin, The inhibitory effect of gankyrin was abrogated by nicotinamide as well as down-regulation of SIRT1, a class III histone deacetylase. Thus, gankyrin binds to NF-KB and suppresses its activity at the transcription level by modulating acetylation via SIRT1. (C) 2007 Elsevier Inc. All rights reserved.