The centrosomal protein tax1 binding protein 2 is a novel tumor suppressor in hepatocellular carcinoma regulated by cyclin-dependent kinase 2

Authors

  • Wai-Lung Lai,

    1. Departments of Anatomy, The University of Hong Kong, Hong Kong, China
    2. Center for Cancer Research, The University of Hong Kong, Hong Kong, China
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  • Wing-Yan Hung,

    1. Departments of Anatomy, The University of Hong Kong, Hong Kong, China
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  • Leo Lap-Yan Wong,

    1. Departments of Anatomy, The University of Hong Kong, Hong Kong, China
    2. Center for Cancer Research, The University of Hong Kong, Hong Kong, China
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  • Yuan Zhou,

    1. Departments of Anatomy, The University of Hong Kong, Hong Kong, China
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  • Veronica Yee-Law Leong,

    1. Departments of Anatomy, The University of Hong Kong, Hong Kong, China
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  • Joyce Man-Fong Lee,

    1. Departments of Pathology, The University of Hong Kong, Hong Kong, China
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  • Irene Oi-Lin Ng,

    1. Departments of Pathology, The University of Hong Kong, Hong Kong, China
    2. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
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  • Dong-Yan Jin,

    1. Departments of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
    2. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
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  • Yick-Pang Ching

    Corresponding author
    1. Departments of Anatomy, The University of Hong Kong, Hong Kong, China
    2. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
    3. Center for Cancer Research, The University of Hong Kong, Hong Kong, China
    • Department of Anatomy, The University of Hong Kong, Room L1-43, Laboratory Block, Faculty of Medicine Building, Hong Kong, China
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    • fax: 852-28170857


  • Potential conflict of interest: Nothing to report.

  • This work was supported by The Hong Kong Research Grants Council (HKU763509 and HKU7/CRF/09), The University of Hong Kong (Small Project Funding 201007176079; to W-L.L. and Y-P.C.), and The S.K. Yee Medical Research Fund 2011 (to D-Y.J. and Y-P.C.). I.O-L.N. is a Loke Yew Professor in Pathology.

Abstract

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. (HEPATOLOGY 2012;56:1770–1781)

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