Targeting the proteasome-associated deubiquitinating enzyme USP14 impairs melanoma cell survival and overcomes resistance to MAPK-targeting therapies

Advanced cutaneous melanoma is one of the most challenging cancers to treat because of its high plasticity, metastatic potential and resistance to treatment. New targeted therapies and immunotherapies have shown remarkable clinical efficacy. However, such treatments are limited to a subset of patients and relapses often occur, warranting validation of novel targeted therapies. Post-translational modification of proteins by ubiquitin coordinates essential cellular functions, including ubiquitin-proteasome system (UPS) function and protein homeostasis. Deubiquitinating enzymes (DUBs) have been associated to multiple diseases, including cancer. However, their exact involvement in melanoma development and therapeutic resistance remains poorly understood. Using a DUB trap assay to label cellular active DUBs, we have observed an increased activity of the proteasome-associated DUB, USP14 (Ubiquitin-specific peptidase 14) in melanoma cells compared to melanocytes. Our survey of public gene expression databases indicates that high expression of USP14 correlates with melanoma progression and with a poorer survival rate in metastatic melanoma patients. Knockdown or pharmacological inhibition of USP14 dramatically impairs viability of melanoma cells irrespective of the mutational status of BRAF, NRAS or TP53 and their transcriptional cell state, and overcomes resistance to MAPK-targeting therapies both in vitro and in human melanoma xenografted mice. At the molecular level, we find that inhibition of USP14 rapidly triggers accumulation of poly-ubiquitinated proteins and chaperones, mitochondrial dysfunction, ER stress, and a ROS production leading to a caspase-independent cell death. Our results provide a rationale for targeting the proteasome-associated DUB USP14 to treat and combat melanomas.

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