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Stopping melanoma metastasis with fucose
Metastatic melanoma is particularly challenging to treat. Lau et al. found that activation of the transcription factor ATF2 by the kinase PKCε, which was more prevalent in advanced-stage melanomas than in primary melanocytes or early-stage tumors, promoted the metastatic behavior of melanoma cells in culture and in mice. ATF2 repressed the expression of the gene encoding fucokinase (FUK), an enzyme that promotes global protein fucosylation. Supplementing drinking water with dietary fucose suppressed the growth and metastasis of melanoma in mice, likely by promoting protein fucosylation, which enhanced cell adhesion and reduced cell migration. Thus, inhibiting PKCε or ATF2 activity or increasing protein fucosylation in tumor cells may be therapeutic for melanoma patients.
Abstract
Melanoma is one of the most lethal skin cancers worldwide, primarily because of its propensity to metastasize. Thus, the elucidation of mechanisms that govern metastatic propensity is urgently needed. We found that protein kinase Cε (PKCε)–mediated activation of activating transcription factor 2 (ATF2) controls the migratory and invasive behaviors of melanoma cells. PKCε-dependent phosphorylation of ATF2 promoted its transcriptional repression of the gene encoding fucokinase (FUK), which mediates the fucose salvage pathway and thus global cellular protein fucosylation. In primary melanocytes and cell lines representing early-stage melanoma, the abundance of PKCε-phosphorylated ATF2 was low, thereby enabling the expression of FUK and cellular protein fucosylation, which promoted cellular adhesion and reduced motility. In contrast, increased expression of the gene encoding PKCε and abundance of phosphorylated, transcriptionally active ATF2 were observed in advanced-stage melanomas and correlated with decreased FUK expression, decreased cellular protein fucosylation, attenuated cell adhesion, and increased cell motility. Restoring fucosylation in mice either by dietary fucose supplementation or by genetic manipulation of murine Fuk expression attenuated primary melanoma growth, increased the number of intratumoral natural killer cells, and decreased distal metastasis in murine isograft models. Tumor microarray analysis of human melanoma specimens confirmed reduced fucosylation in metastatic tumors and a better prognosis for primary melanomas that had high abundance of fucosylation. Thus, inhibiting PKCε or ATF2 or increasing protein fucosylation in tumor cells may improve clinical outcome in melanoma patients.
