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The recruitment of histone acetyltransferases and histone deacetylases (HDACs) is considered as a key element in the dynamic regulation of many genes playing important roles in cellular proliferation. Accumulated evidences have established that aberrant regulation of HDACs is one of major causes for development of human malignancies. Recent study has suggested that increased HDAC2 expression was found and was enhanced by loss of APC in the human colorectal cancer. Since aberrant regulation of Wnt signaling is also one of most important tumorigenic pathway in hepatocarcinogenesis, we evaluated expression pattern of HDAC2 as well as key molecules of Wnt pathway including β-catenin, Pin1, c-Myc, cyclin D1 in surgically resected hepatocellular carcinomas (HCCs) to address HDAC2 regulated by Wnt signaling as a potential therapeutic target in HCCs. HDAC2 was appeared to be highly over-expressed in most tumor tissues compared to normal liver. This implies that increased HDAC2 expression may explain the contribution of HDAC2 in the development of sub-set HCCs. However, at least, the activation of Wnt signaling contributed by β-catenin accumulation does not seem to be the regulatory signaling for inappropriate transcriptional activation of HDAC2 by the fact that gene silencing of those Wnt pathway genes, β-catenin, c-Myc, cyclin D1 did not affect expression of HDAC2. In contrast, targeted disruption of HDAC2 genes by using siRNA techniques resulted in growth inhibition of Hep3b cells. Taken together, we suggest that the aberrant regulation of HDAC2 expression which independent of Wnt/ β-catenin signaling pathways directly relate to development of HCCs.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]