Merlin Is a Negative Regulator of Human Melanoma Growth

Abstract

Merlin is encoded by the neurofibromatosis type 2 (NF2) gene and is a member of the Band 4.1 protein family. This protein acts as a linker that connects cell surface proteins to the actin cytoskeleton. Defects 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, NF2 is mutated and/or merlin expression is reduced or lost in numerous non-NF2 associated tumors, including melanoma. However, the role of merlin in human melanoma growth and the mechanism underlying its effect are currently unknown. In the present study, we show that merlin knockdown enhances melanoma cell proliferation, migration, and invasion in vitro and that decreased merlin expression promotes subcutaneous melanoma growth in immunocompromised mice. Concordantly, we find that increased expression of merlin in a metastatic melanoma cell line reduced their in vitro migration and proliferation, and diminished their ability to grow in an anchorage independent manner. Increased merlin expression also inhibits in vivo growth of these melanoma cells. Lastly, we demonstrate that higher merlin levels in human melanoma cells promote the H2O2-induced activation of MST1/2 Ser/Thr kinases, which are known tumor suppressors in the Hippo signaling pathway. Taken together, these results provide for the first time evidence that merlin negatively regulates human melanoma growth, and that loss of merlin, or impaired merlin function, results in an opposite effect. In addition, we show that increased merlin expression leads to enhanced activation of the MTS1/2 kinases, implying the potential roles of MST1/2 in mediating the anti-melanoma effects of merlin.

Functional interdependence of NHE1 and merlin in human melanoma cells

“…7). This is consistent with the findings that (i) higher merlin levels are correlated with a decrease in MeWo human melanoma cell motility in transwell migration assays (Murray et al 2012) and (ii) overexpression of merlin in B16F10 mouse melanoma cells reduces their metastatic activity (Galcheva-Gargova et al 2008). Also in schwannoma merlin has been shown to inhibit migratory activity (Stamenkovic and Yu 2010).…”

“…Like the ERM proteins, merlin can function as a structural link between numerous membrane transport proteins and the actin cytoskeleton (Sainio et al 1997). Merlin is a tumor suppressor protein whose inactivating mutations were found in a wide variety of nerve and non-nervous tumors, such as neurofibromas and schwannomas (Stamenkovic and Yu 2010) or colon (Cacev et al 2014), prostate cancer (Horiguchi et al 2008), and melanoma (Murray et al 2012). In various cell types, merlin deficiency leads to an increase in cell proliferation, a decrease in both cell-cell adhesion and contact inhibition, and an elevated cell motility (Stamenkovic and Yu 2010;Murray et al 2012).…”

67-kDa Laminin Receptor-dependent Protein Phosphatase 2A (PP2A) Activation Elicits Melanoma-specific Antitumor Activity Overcoming Drug Resistance

“…PP2A induces inactivation of CPI-17 by promoting dephosphorylation at Thr-38 (23). Although Merlin was previously shown to be important for inhibition of melanoma cell growth, the promotion of Merlin activity has not been reported (24). Treatment with EGCG induced dephosphorylation of Merlin in a time-dependent manner ( Fig.…”

Loss of Merlin induces metabolomic adaptation that engages dependence on Hedgehog signaling

“…Originally described as mutated in the context of neurofibromatosis and tumors of the nervous system, Merlin has more recently been demonstrated to function as a tumor suppressor in mesothelioma, melanoma, and breast cancer123456. Multiple post-translational modifications and interactions with cytoskeletal proteins regulate and execute Merlin’s tumor suppressor function.…”