Posttranscriptional control of the chemokine receptor CXCR4 expression in cancer cells

CXCR4is a chemokine receptorthat is overexpressed in certain cancer types and involved in migration toward distant organs. The molecular mechanisms underlying CXCR4expression in invasive cancer, particularly posttranscriptional regulation, are poorly understood. Here, we find that CXCR4harbors AU-rich elements(AREs) in the 3′-untranslated region (3′-UTR) that bind and respond to the RNA-binding proteins, tristetraprolin(TTP/ ZFP36) and HuR (ELAVL1). Different experimental approaches, including RNA immunoprecipitation, 3′-UTR reporter, RNA shift and messenger RNA (mRNA) half-life studies confirmed functionality of the CXCR4ARE. Wild-type TTP, but not the zinc finger mutant, C124R, was able to bind CXCR4mRNA and ARE. In the invasive breast cancer phenotype, aberrant expression of CXCR4is linked to both TTP deficiency and HuR overexpression. HuR silencing led to decreased CXCR4mRNA stability and expression, and significant reduction in migration of the cells toward the CXCR4ligand, CXCL12. Derepressionof TTP using miR-29a inhibitor led to significant reduction in CXCR4mRNA stability, expression and migration capability of the cells. The study shows that CXCR4is regulated by ARE-dependent posttranscriptional mechanisms that involve TTP and HuR, and that aberration in this pathway helps cancer cells migrate toward the CXCR4ligand. Targeting posttranscriptional control of CXCR4expression may constitute an alternative approach in cancer therapy.