MALT1 Promotes Melanoma Progression Through JNK/c-Jun Signaling

Mucosa-associated lymphoma antigen 1 (MALT1) is a lymphoma oncogene that regulates signal transduction as a paracaspase and an adaptor protein. Yet, the role of MALT1 in other solid cancers such as melanoma is not well-understood. Here, we demonstrate that MALT1 is overexpressed in malignant melanoma cells, and predicts a poor disease-free survival. MALT1 inhibition via shRNA-mediated gene silencing or pharmacologically with MI-2 compound markedly reduced cell growth and migration of A2058 and A375 melanoma cell lines in vitro. Subcutaneous tumor growth analysis revealed that MALT1 gene silencing significantly reduced tumor growth and metastasis to the lung. Consistently, the subcutaneous tumors with MALT1 loss had increased cell apoptosis and decreased proliferation. In addition, these tumors showed signs of mesenchymal-epithelial transition as indicated by the upregulation of E-cadherin and downregulation of N-cadherin and β1-intergrin. Further molecular analysis revealed that MALT1 is required for c-Jun and nuclear factor-κB (NF-κB) activation by tumor necrosis factor-α. Forced expression of the c-Jun upstream activator MKK7 reversed the cell growth and migration defects caused by MALT1 loss. In contrast, NF-κB activation via expression of p65ER, a fusion protein containing NF-κB p65 and the tamoxifen-responsive mutant estrogen receptor, induced minimal effects on cell proliferation, but diminished cell death induced by MALT1 loss and TRAIL treatment. Together, these findings demonstrate that MALT1 promotes melanoma cell proliferation and motility through JNK/c-Jun, and enhances melanoma cell survival through NF-κB, underscoring MALT1 as a potential therapeutic target and biomarker for malignant melanoma.