CXCR4 is a chemokine receptor that is overexpressed in certain cancer types and 
involved in migration toward distant organs. The molecular mechanisms underlying 
CXCR4 expression in invasive cancer, particularly posttranscriptional 
regulation, are poorly understood. Here, we find that CXCR4 harbors 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 CXCR4 ARE. Wild-type TTP, but not the zinc finger mutant, 
C124R, was able to bind CXCR4 mRNA and ARE. In the invasive breast cancer 
phenotype, aberrant expression of CXCR4 is linked to both TTP deficiency and HuR 
overexpression. HuR silencing led to decreased CXCR4 mRNA stability and 
expression, and significant reduction in migration of the cells toward the CXCR4 
ligand, CXCL12. Derepression of TTP using miR-29a inhibitor led to significant 
reduction in CXCR4 mRNA stability, expression and migration capability of the 
cells. The study shows that CXCR4 is regulated by ARE-dependent 
posttranscriptional mechanisms that involve TTP and HuR, and that aberration in 
this pathway helps cancer cells migrate toward the CXCR4 ligand. Targeting 
posttranscriptional control of CXCR4 expression may constitute an alternative 
approach in cancer therapy.