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.