Posttranslational modifications of CXCR4: implications in cancer metastasis

Xiyun Deng, Juan Xu, Guangchun He, Yongguang Tao, Tao Yang, Xiaoning Peng, Ya Cao

Abstract


CXCR4, the most widely expressed chemokine receptor in solid malignancies, has been implicated in cancer metastasis. However, how the activity of CXCR4 is regulated during carcinogenesis especially at the metastatic stage remains largely unknown. As with other G protein-coupled receptors, CXCR4 is subjected to posttranslational medications such as phosphorylation, ubiquitination, glycosylation, and sulfation. These posttranslational modifications contribute significantly to the heterogeneity of CXCR4 in terms of intracellular location, signaling, and functionality. We have shown that the difference in the sulfation level of CXCR4 is responsible for, if not all, the difference in the activities of CXCR4 between the highly metastatic and non-metastatic nasopharyngeal carcinoma (NPC) cell lines. Molecular mechanistic studies revealed that the Epstein-Barr virus-encoded oncoprotein LMP1 induces the expression of tyrosylprotein sulfotransferase 1 (TPST-1) through nuclear translocation of the epidermal growth factor receptor. This LMP1-regulated TPST-1 expression accounts for tyrosine sulfation of CXCR4 and is associated with the metastatic phenotype of NPC cell lines. Finally, in NPC patient specimens, there was a positive correlation between the expression of LMP1 and TPST-1 and the metastatic potential of NPC. Our findings provide the first evidence that the posttranslational modification of a chemokine receptor plays a role in cancer metastatic progression. Understanding the role of posttranslational modifications of chemokine receptors in cancer biology may provide new insights for developing attractive therapeutic targets in cancer therapy.

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DOI: http://dx.doi.org/10.14800/rci.63

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