The short chain fatty acid (SCFA) butyrate (BA) and other histone deacetylase (HDAC) inhibitors can rapidly induce cell cycle arrest and differentation of colon cancer cell lines. We found that butyrate and the specific HDAC inhibitor trichostatin A (TSA) can reprogram the NF-(kappa)B response in colon cancer cells. Specifically, TNF-alpha activation is suppressed in butyrate-differentiated cells, whereas IL-1beta activation is largely unaffected. To gain insight into the relationship between butyrate-induced differentiation and NF-(kappa)B regulation, we determined the impact of butyrate on proteasome activity and subunit expression. Interestingly, butyrate and TSA reduced the cellular proteasome activity in colon cancer cell lines. The drop in proteasome activity results from the reduced expression of the catalytic beta-type subunits of the proteasome at both the protein and mRNA level. The selective impact of HDAC inhibitors on TNF-alpha-induced NF-(kappa)B activation appears to relate to the fact that the TNF-alpha-induced activation of NF-(kappa)B is mediated by the proteasome, whereas NF-kappaB activation by IL-1beta is largely proteasome-independent. These findings indicate that cellular differentation status and/or proliferative capacity can significantly impact proteasome activity and selectively alter NF-(kappa)B responses in colon cancer cells. This information may be useful for the further development and targeting of HDAC inhibitors as anti-neoplastic and anti-inflammatory agents.