Abstract
FUT8-mediated core fucosylation of L1CAM drives melanoma metastasis.
Major finding: FUT8-mediated core fucosylation of L1CAM drives melanoma metastasis.
Approach: Glycomic profiling of matched primary tumors and metastases identified prometastasis genes.
Impact: Inhibition of FUT8-driven glycosylation may be a potential therapeutic strategy to prevent metastasis.
Dysregulation of glycosylation, which is controlled by glycosyltransferases and glycosidases, is frequently observed in cancer and has been shown to promote tumor progression and metastasis, but the precise roles of specific glycosylation enzymes in promoting the malignant phenotype have not been fully elucidated, particularly in human melanoma. To systematically analyze glycosylation in melanoma, Agrawal and colleagues generated glycomic profiles of matched patient primary tumors and metastases using lectin microarrays. Integration of the microarray data with publicly available transcriptomic data revealed that melanoma metastases exhibited overexpression of the core fucosyltransferase 8 (FUT8) and decreased expression of the α-1,2 fucosylation enzymes FUT1 and FUT2. RNAi knockdown experiments confirmed that loss of either FUT1 or FUT2 promoted invasion in vitro, whereas loss of FUT8 abrogated core fucosylation and invasion in vitro and reduced metastastic potential in vivo. Further, doxycycline-induced knockdown of FUT8 reduced the growth of established melanoma metastatic foci, suggesting that FUT8 is required for metastatic colonization. Knockdown of transcription factors predicted to bind the FUT8 promoter revealed that TGIF2 regulates FUT8 transcription in melanoma cells. Proteomic profiling of core-fucosylated membrane proteins identified potential FUT8 targets, including L1 cell adhesion molecule (L1CAM) and neuropilin 2 (NRP2), which were enriched for metastasis-associated functions. L1CAM or NRP2 exhibited decreased binding to the lectin LcH, which specifically binds to core-fucosylated proteins, after knockdown of FUT8, thus confirming that FUT8 mediates core fucosylation of L1CAM and NRP2. Overexpression of L1CAM or FUT8 induced increased invasion in vitro, which was respectively ablated upon FUT8 or L1CAM silencing, and overexpression of FUT8 promoted the increased core fucosylation of L1CAM, resulting in the inhibition of plasmin-mediated cleavage of L1CAM. These results identify key glycomic drivers of melanoma metastasis and suggest that inhibition of FUT8 and its targets is a potential antimetastasis strategy.
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