HDAC2 deficiency sensitizes colon cancer cells to TNF[alpha]-induced apoptosis through inhibition of NF-[kappa]B activity

HDAC inhibitors exert potent anti-tumorigenic and anti-inflammatory activity. Their effects are selective for transformed cells, and we recently demonstrated that transformation of epithelial cells with k-Ras sensitizes cells to HDACi induced apoptosis. The aim of this study was to determine whether the ability of HDACi to modulate signaling by a major pro-inflammatory cytokine, TNF[alpha], is also restricted to cells that harbor mutant k-Ras. We used the system of two isogenic cell lines that differ by the presence of mutant k-Ras, HCT116 and Hke3 cells. Treatment of cells with TNF[alpha] alone did not induce apoptosis; however HDACi potentiated TNF[alpha]-induced apoptosis in both HCT116 and Hke3 cells. Thus, the ability of HDACi to sensitize cells to TNF[alpha]-induced apoptosis appears to be k-Ras independent. We demonstrated that HDACi inhibited TNF[alpha]-induced NF-[kappa]B transcriptional and DNA binding activity in both cell lines, underlying the increased apoptosis in cells treated with both agents. We showed that overexpression of HDAC2 enhanced TNF[alpha]-induced NF-[kappa]B activity and that silencing of HDAC2 decreased NF-[kappa]B activity. Finally, silencing of HDAC2 expression was sufficient to sensitize colon cancer cells to TNF[alpha]-induced apoptosis. The ability of HDACi to interfere with NF-[kappa]B activity is likely to contribute to their potent anti-tumorigenic and anti-inflammatory activity. [PUBLICATION ABSTRACT]