1. Oncogenic potential of CK2α and its regulatory role in EGF-induced HDAC2 expression in human liver cancer.
- Author
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Kim HS, Chang YG, Bae HJ, Eun JW, Shen Q, Park SJ, Shin WC, Lee EK, Park S, Ahn YM, Park WS, Lee JY, and Nam SW
- Subjects
- Carcinoma, Hepatocellular metabolism, Casein Kinase II antagonists & inhibitors, Casein Kinase II genetics, Casein Kinase II metabolism, Cell Line, Tumor, Cell Proliferation, Cohort Studies, ErbB Receptors metabolism, Histone Deacetylase 2 genetics, Humans, Liver metabolism, Mutant Proteins antagonists & inhibitors, Mutant Proteins metabolism, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Phosphorylation, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, RNA Interference, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Signal Transduction, Survival Analysis, Carcinogenesis, Epidermal Growth Factor metabolism, ErbB Receptors agonists, Gene Expression Regulation, Neoplastic, Histone Deacetylase 2 metabolism, Liver Neoplasms metabolism
- Abstract
Histone deacetylase 2 (HDAC2) is aberrantly regulated and plays a pivotal role in the development of hepatocellular carcinoma (HCC) through regulation of cell-cycle components at the transcriptional level, but the underlying mechanism leading to oncogenic HDAC2 remains unknown. In this study, we show that expression of CK2α (casein kinase II α subunit) was up-regulated in a large cohort of human HCC patients, and that high expression of CK2α was significantly associated with poor prognosis of HCC patients in terms of five-year overall survival. It was also found that CK2α over-expression positively correlated with HDAC2 over-expression in a subset of HCCs. We observed that treatment with epidermal growth factor (EGF) elicited an increase in CK2α expression and Akt phosphorylation, causing induction of HDAC2 expression in liver cancer cells. It was also observed that ectopic expression of dominant-negative CK2α blocked EGF-induced HDAC2 expression, and that ectopic CK2α expression attenuated the suppressive effect of Akt knockdown on HDAC2 expression in liver cancer cells. Targeted disruption of CK2α influenced the cell cycle, causing a significant increase in the number of liver cancer cells remaining in G₂/M phase, and suppressed growth via repression of Cdc25c and cyclin B in liver cancer cells. Taken together, our findings suggest the oncogenic potential of CK2α in liver tumorigenesis. Furthermore, a regulatory mechanism for HDAC2 expression is proposed whereby EGF induces transcriptional activation of HDAC2 by CK2α/Akt activation in liver cancer cells. Therefore, this makes CK2α a promising target in cancer therapy.
- Published
- 2014
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