The cylindromatosis gene (CYLD) was identified as a tumor suppressor gene, which 
is mutated in familial cylindromatosis (Brooke-Spiegler syndrome), an 
autosomal-dominant predisposition to multiple tumors of the skin appendages. 
CYLD is a deubiquitinating enzyme acting as a negative regulator of the nuclear 
factor κB (NF-κB) signaling pathway by removing lysine-63-linked polyubiquitin 
chains from NF-κB activating proteins. In order to investigate the role of CYLD 
in apoptotic signaling in human hepatocellular carcinoma (HCC) cells, we first 
studied the expression levels of CYLD in HCC tissues. CYLD expression was lower 
in HCC both at protein and mRNA levels compared to the surrounding non-malignant 
tissue. In order to further study the role of CYLD in the apoptotic sensitivity 
of HCC cells, CYLD was specifically down-regulated in HCC cell lines via RNA 
interference. The specific down-regulation of CYLD resulted in increased 
resistance towards treatment with doxorubicin, 5-fluorouracil and cisplatin. In 
addition, the down-regulation of CYLD in HCC cells decreased the sensitivity 
towards tumor necrosis factor-α-induced apoptosis. The CYLD knockdown also led 
to the degradation of the NF-κB inhibitor, IκB-α, resulting in enhanced NF-κB 
activity in HCC cells. Finally, we found that CYLD expression was triggered by 
the multikinase inhibitor, sorafenib, by the inhibition of Raf-1, as well as by 
the blockage of the pro-survival kinases, MEK (U0126) and the epidermal growth 
factor receptor (AG1478). In summary, we show that CYLD is down-regulated in 
human HCC and is involved in the apoptotic resistance of HCC cells. Our data 
identify the reconstitution of CYLD expression as an attractive approach for 
overcoming resistance to treatment in HCC.