WW45, a Gli1 binding protein, negatively regulated Hedgehog signaling in lung cancer.

Over-expression of Gli1 is very common in lung cancer. However, the underlying molecular mechanism remains largely unknown. Here, using mass spectrum, we have identified WW45 as a binding partner of Gli1. WW45 interacted with Gli1, promoted its ubiquitination and inhibited the expression of its target genes. In the functional studies, WW45 inhibited the growth and migration of lung cancer cells. Knocking down the expression of WW45 promoted the growth and migration of lung cancer cells, which was rescued by down-regulation of Gli1. Moreover, over-expression of WW45 inhibited the tumorigenesis in a de novo lung cancer tumorigenesis mouse model (LKB-Ras) as well as the expression of Gli1. Also over-expression of WW45 improved the survival of these mice. In addition, the expression of WW45 was down-regulated in the clinical lung cancer samples, which was inversely correlated with the expression of Gli1. Taken together, this study demonstrated the suppressive roles of WW45 in lung cancer by inhibiting the Hedgehog/Gli1 signaling.