Tyrosylprotein sulfotransferase-1 and Tyrosine Sulfation of Chemokine Receptor 4 Are Induced by Epstein-Barr Virus Encoded Latent Membrane Protein 1 and Associated With the Metastatic Potential of Human Nasopharyngeal Carcinoma

PLoS One. 2013;8(3):e56114. doi: 10.1371/journal.pone.0056114. Epub 2013 Mar 5.

Abstract

The latent membrane protein 1 (LMP1), which is encoded by the Epstein-Barr virus (EBV), is an important oncogenic protein that is closely related to carcinogenesis and metastasis of nasopharyngeal carcinoma (NPC), a prevalent cancer in China. We previously reported that the expression of the functional chemokine receptor CXCR4 is associated with human NPC metastasis. In this study, we show that LMP1 induces tyrosine sulfation of CXCR4 through tyrosylprotein sulfotransferase-1 (TPST-1), an enzyme that is responsible for catalysis of tyrosine sulfation in vivo, which is likely to contribute to the highly metastatic character of NPC. LMP1 could induce tyrosine sulfation of CXCR4 and its associated cell motility and invasiveness in a NPC cell culture model. In contrast, the expression of TPST-1 small interfering RNA reversed LMP1-induced tyrosine sulfation of CXCR4. LMP1 conveys signals through the epidermal growth factor receptor (EGFR) pathway, and EGFR-targeted siRNA inhibited the induction of TPST-1 by LMP1. We used a ChIP assay to show that EGFR could bind to the TPST-1 promoter in vivo under the control of LMP1. A reporter gene assay indicated that the activity of the TPST-1 promoter could be suppressed by deleting the binding site between EGFR and TPST-1. Finally, in human NPC tissues, the expression of TPST-1 and LMP1 was directly correlated and clinically, the expression of TPST-1 was associated with metastasis. These results suggest the up-regulation of TPST-1 and tyrosine sulfation of CXCR4 by LMP1 might be a potential mechanism contributing to NPC metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Carcinoma
  • Cell Line, Tumor
  • Chemotaxis
  • Flow Cytometry
  • Gene Deletion
  • Genes, Reporter
  • Herpesvirus 4, Human
  • Humans
  • Nasopharyngeal Carcinoma
  • Nasopharyngeal Neoplasms / metabolism*
  • Nasopharyngeal Neoplasms / virology
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • RNA, Small Interfering / metabolism
  • Receptors, CXCR4 / metabolism*
  • Sulfotransferases / metabolism*
  • Tyrosine / metabolism*
  • Viral Matrix Proteins / metabolism*

Substances

  • CXCR4 protein, human
  • EBV-associated membrane antigen, Epstein-Barr virus
  • RNA, Small Interfering
  • Receptors, CXCR4
  • Viral Matrix Proteins
  • Tyrosine
  • Sulfotransferases
  • protein-tyrosine sulfotransferase

Grant support

This work was supported by the National Basic Research Program of China (2009CB521801, 2011CB504300) and the National Nature Science Foundation of China (30771966, 30930101, 81171881). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.