MicroRNA-24 regulates XIAP to reduce the apoptosis threshold in cancer cells

MicroRNAs have been implicated as important mediators of cancer cell homeostasis, and accumulating data suggest compelling roles for them in the apoptosis pathway. X-linked inhibitor of apoptosis protein (XIAP) is a potent caspase inhibitor and an important barrier to apoptotic cell death, but the mechanisms which determine the diverse range of XIAP expression seen in cancer remains unclear. In this study, we present evidence that miR-24 directly targets the 3′UTR of the XIAP mRNA to exert translational repression. Using a heuristic algorithm of bioinformatics analysis and in vitro screening, we identified miR-24 as a candidate regulator of XIAP expression. Array CGH and SKY analysis reveal that genomic copy number loss at the miR-24 locus is concordant with loss of endogenous miR-24 in cancer cells. Using a luciferase construct of the XIAP 3′UTR, we showed that miR-24 specifically coordinates to the XIAP mRNA. And interference with miR-24’s binding of the critical seed region, resulting from site-directed mutagenesis of the 3′UTR, significantly abrogated miR-24’s effects on XIAP expression. Moreover, miR-24 over-expression can overcome apoptosis-resistance in cancer cells via down-regulation of XIAP expression, and the resulting cancer cell death induced by TRAIL is executed by the canonical caspase-mediated apoptosis pathway. In summary, our data suggest a novel mechanism by which miR-24 directly modulates XIAP expression level and consequently the apoptosis threshold in cancer cells.