Merlin is a cytoskeletal linker protein encoded by the neurofibromatosis type 2 (NF2) gene. Like the other Band 4.1 protein family members, it serves to connect cell surface proteins to the actin cytoskeleton. Defects in the protein caused by mutations of the NF2 gene give rise to NF2 disease, which is generally characterized by the formation of bilateral vestibular schwannomas and, to a lesser extent, meningiomas and ependymomas. In addition to these tumor types, merlin has been shown to be mutated and/or merlin protein expression lost in other cancers including mesothelioma, thyroid cancers, and melanomas, albeit to a lesser extent. In the current study, we set out to elucidate the role of merlin in the progression of human melanoma. We first show that merlin knockdown enhances melanoma cell migration and invasion in vitro. Furthermore, we show that decreased merlin expression leads to increased subcutaneous melanoma growth in immuno-compromised mice. Tumors derived from merlin knockdown cells display border regions that are generally less well defined, with cases in which tumor cells are visible in the surrounding dermis and adipose tissue, which is consistent with the more invasive phenotype observed in vitro upon merlin knockdown. To compliment these knockdown experiments we overexpressed merlin in a metastatic melanoma cell line. Upon increased merlin expression, the melanoma cells exhibit decreased in vitro migration, invasion, and proliferation. These cells also display a diminished ability to form anchorage independent colonies in soft agar. Additionally, increased merlin expression inhibits in vivo subcutaneous growth of the melanoma cells in our xenograft experiments. Lastly, we surveyed several signaling pathways to identify a mechanism that exerts the negative regulatory effect of merlin on melanoma growth. We found that merlin protein levels in human melanoma cells are correlated with the extent of induced activation of the known tumor suppressors in the Hippo signaling pathway, MST1/2 Ser/Thr kinases, which have been shown to function downstream of merlin in other cell types. Taken together, these results provide evidence for the first time that merlin is a negative regulator of human melanoma progression and that it may exert its inhibitory effects through the activation of the MST1/2 kinases.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3987. doi:1538-7445.AM2012-3987