Therapies directed to specific molecular targets are still unmet for triple-negative breast cancer (TNBC) patients. Deubiquitinases (DUBs) are emerging drug targets. The identification of a highly... Show moreTherapies directed to specific molecular targets are still unmet for triple-negative breast cancer (TNBC) patients. Deubiquitinases (DUBs) are emerging drug targets. The identification of a highly active DUBs in TNBC may lead to novel therapies.\n biochemical methods. A specific inhibitor was synthesised and its biochemical and biological functions were assessed in a range of assays. Finally, we used patient sera samples to investigate clinical correlations.\nTwo DUB activity profiling approaches identified UCHL1 as being highly active in TNBC cell lines and aggressive tumors. Functionally, UCHL1 promoted metastasis in zebrafish and murine breast cancer xenograft models. Mechanistically, UCHL1 facilitates TGFβ signaling-induced metastasis by protecting TGFβ type I receptor and SMAD2 from ubiquitination. We found that these responses are potently suppressed by the specific UCHL1 inhibitor, 6RK73. Furthermore, UCHL1 levels were significantly increased in TNBC patient sera, and highly enriched in sera exosomes as well as TNBC cell conditioned media. UCHL1 enriched exosomes stimulated breast cancer migration and extravasation, suggesting that UCHL1 may act in a paracrine manner to promote tumor progression.\nOur DUB activity profiling identified UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis and may provide a potential target for TNBC treatment. Show less
