Hepatitis B virus X protein induces IKKα nuclear translocation via Akt-Dependent phosphorylation to promote the motility of hepatocarcinoma cells

• Published in: Journal of cellular physiology Vol. 227; no. 4; pp. 1446 - 1454
• Main Authors: Huang, Wei-Chien, Chen, Wen-Shu, Chen, Yun-Ju, Wang, Li-Yun, Hsu, Sheng-Chieh, Chen, Ching-Chow, Hung, Mien-Chie
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-04-2012
• Subjects: Active Transport, Cell Nucleus - drug effects; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - physiopathology; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - genetics; Cell Movement - physiology; Disease Progression; HEK293 Cells; Hep G2 Cells; Hepatitis B virus - pathogenicity; Humans; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; Liver Neoplasms - etiology; Liver Neoplasms - pathology; Liver Neoplasms - physiopathology; Mutagenesis, Site-Directed; Neoplasm Invasiveness - pathology; Neoplasm Invasiveness - physiopathology; Nuclear Localization Signals - genetics; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Trans-Activators - toxicity; Ubiquitination; Viral Proteins - toxicity
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.22860

Hepatitis B virus (HBV) X protein (HBx) has been implicated in HBV‐associated carcinogenesis through activation of IκB kinase (IKK)/nuclear factor kappa B (NF‐κB) signaling pathway. Besides activating NF‐κB in the cytoplasm, IKKα was found in the nucleus to regulate gene expression epigenetically in response to various stimuli. However, it is unknown whether nuclear IKKα plays a role in HBx‐associated tumor progression. Moreover, the molecular mechanism underlying IKKα nuclear transport also remains to be elucidated. Here, we disclosed HBx as a new inducer of IKKα nuclear transport in hepatoma cells. HBx induced IKKα nuclear transport in an Akt‐dependent manner. HBx‐activated Akt promoted IKKα nuclear translocation via phosphorylating its threonine‐23 (Thr23). In addition, IKKα ubiquitination enhanced by HBx and Akt also contributed to the IKKα accumulation in the nucleus, indicating the involvement of ubiquitination in Akt‐increased IKKα nuclear transport in response to HBx. Furthermore, inhibition of IKKα nuclear translocation by mutation of its nuclear localization signal and Thr23 diminished IKKα‐dependent cell migration. Taken together, our findings shed light on the molecular mechanism of IKKα nuclear translocation and provide a potential role of nuclear IKKα in HBx‐mediated hepatocellular carcinoma (HCC) progression. J. Cell. Physiol. 227: 1446–1454, 2012. © 2011 Wiley Periodicals, Inc.