Melanoma progression is generally associated with increased transcriptional activity mediated by the Yes‐associated protein (YAP). Mechanical signals from the extracellular matrix are sensed by YAP, which then activates the expression of proliferative genes, promoting melanoma progression and drug resistance. Which extracellular signals induce mechanotransduction, and how this is mediated, is not completely understood. Here, using secretome analyses, we reveal the extracellular accumulation of amyloidogenic proteins, i.e. premelanosome protein (PMEL), in metastatic melanoma, together with proteins that assist amyloid maturation into fibrils. We also confirm the accumulation of amyloid‐like aggregates, similar to those detected in Alzheimer disease, in metastatic cell lines, as well as in human melanoma biopsies. Mechanistically, beta‐secretase 2 (BACE2) regulates the maturation of these aggregates, which in turn induce YAP activity. We also demonstrate that recombinant PMEL fibrils are sufficient to induce mechanotransduction, triggering YAP signaling. Finally, we demonstrate that BACE inhibition affects cell proliferation and increases drug sensitivity, highlighting the importance of amyloids for melanoma survival, and the use of beta‐secretase inhibitors as potential therapeutic approach for metastatic melanoma.
BACE1 and BACE2 belong to a class of proteases called β-secretases involved in ectodomain shedding of different transmembrane substrates. These enzymes have been extensively studied in Alzheimer's disease as they are responsible for the processing of APP in neurotoxic Aβ peptides. These proteases, especially BACE2, are overexpressed in tumors and correlate with poor prognosis. Recently, different research groups tried to address the role of BACE1 and 2 in cancer development and progression. In this review, we summarize the latest findings on β-secretases in cancer, highlighting the mechanisms that build the rationale to propose inhibitors of these proteins as a new line of treatment for different tumor types.
Melanoma progression is generally associated to increased Yes-associated protein (YAP) mediated transcription. Actually, mechanical signals from the extracellular matrix are sensed by YAP, which activates proliferative genes expression, promoting melanoma progression and drug resistance. Which and how extracellular signals induce mechanotransduction is not completely understood.Herein, by secretome studies, we revealed an extracellular accumulation of amyloidogenic proteins, i.e. premelanosome protein (PMEL), together with proteins that assist amyloids maturation into fibrils. Indeed, we confirmed the presence of amyloid-like aggregates similar to those detected in Alzheimer disease. These aggregates were enriched in metastatic cell lines as well as in human melanoma biopsies, compared to their primitive counterpart. Mechanistically, we proved that beta-secretase (BACE) regulates the maturation of these aggregates and that its inhibition hampers YAP activity. Moreover, recombinant PMEL fibrils induce per se mechanotransduction promoting YAP activation. Finally, BACE inhibition affects cell proliferation and increases drug sensitivity. These results highlight the importance of amyloids for melanoma survival and the potential of beta-secretase inhibitors as new therapeutic approach to metastatic melanoma.
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