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The centrosomal protein tax1 binding protein 2 is a novel tumor suppressor in hepatocellular carcinoma regulated by cyclin‐dependent kinase 2
Author(s) -
Lai WaiLung,
Hung WingYan,
Wong Leo LapYan,
Zhou Yuan,
Leong Veronica YeeLaw,
Lee Joyce ManFong,
Ng Irene OiLin,
Jin DongYan,
Ching YickPang
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25851
Subject(s) - cancer research , suppressor , gene silencing , tumor suppressor gene , biology , hccs , effector , small interfering rna , protein kinase a , kinase , cyclin dependent kinase , cyclin dependent kinase 2 , hepatocellular carcinoma , carcinogenesis , microbiology and biotechnology , transfection , cell cycle , gene , biochemistry
Deregulation of cellular‐signaling pathways by the inactivation of tumor‐suppressor genes is one of the major causes of hepatocellular carcinoma (HCC). In this study, we identified Tax1 binding protein 2 (TAX1BP2) as a novel tumor‐suppressor gene in HCC. TAX1BP2 transcript was frequently underexpressed (42.2% with T/NT <0.5; P < 0.03) in HCCs, and underexpression of TAX1BP2 was associated with poorer overall survival rates in patients after surgical resection. An effector domain (ED) for TAX1BP2 tumor‐suppressor activity was mapped to the amino‐acid residues 267‐756. Transient or stable expression of either full‐length or ED of TAX1BP2 significantly suppressed HCC cell tumorigenicity through the activation of the p38/p53/p21 pathway. In contrast, silencing of TAX1BP2 by short interfering RNA remarkably suppressed the activation of the p38/p53/p21 pathway. Finally, phosphorylation of TAX1BP2 at serine‐763 by cyclin‐dependent kinase (CDK)2 abolished the TAX1BP2‐mediated p38 activation and tumor‐suppressive activity, indicating that TAX1BP2 can adapt CDK2 signaling to the p38/p53/p21 pathway. Conclusion : Taken together, our data provide the first evidence that TAX1BP2 is a CDK2‐regulated tumor‐suppressor gene in HCC and is a novel activator of the p38/p53/p21 pathway. (H EPATOLOGY 2012;56:1770–1781)