Article first published online: 17 SEP 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 5, pages 1770–1781, November 2012
How to Cite
Lai, W.-L., Hung, W.-Y., Wong, L. L.-Y., Zhou, Y., Leong, V. Y.-L., Lee, J. M.-F., Ng, I. O.-L., Jin, D.-Y. and Ching, Y.-P. (2012), The centrosomal protein tax1 binding protein 2 is a novel tumor suppressor in hepatocellular carcinoma regulated by cyclin-dependent kinase 2. Hepatology, 56: 1770–1781. doi: 10.1002/hep.25851
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.
- Issue published online: 31 OCT 2012
- Article first published online: 17 SEP 2012
- Accepted manuscript online: 18 MAY 2012 11:50AM EST
- Manuscript Accepted: 8 MAY 2012
- Manuscript Received: 26 JAN 2012
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)