Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation

Qian Liu, Emma Adhikari, Daniel K. Lester, Bin Fang, Joseph O. Johnson, Yijun Tian, Andrea T. Mockabee-Macias, Victoria Izumi, Kelly M. Guzman, Michael G. White, John M. Koomen, Jennifer A. Wargo, Jane L. Messina, Jianfei Qi and Eric K. Lau ()
Additional contact information
Qian Liu: H. Lee Moffitt Cancer Center & Research Institute
Emma Adhikari: H. Lee Moffitt Cancer Center & Research Institute
Daniel K. Lester: H. Lee Moffitt Cancer Center & Research Institute
Bin Fang: H. Lee Moffitt Cancer Center & Research Institute
Joseph O. Johnson: H. Lee Moffitt Cancer Center & Research Institute
Yijun Tian: H. Lee Moffitt Cancer Center & Research Institute
Andrea T. Mockabee-Macias: H. Lee Moffitt Cancer Center & Research Institute
Victoria Izumi: H. Lee Moffitt Cancer Center & Research Institute
Kelly M. Guzman: H. Lee Moffitt Cancer Center & Research Institute
Michael G. White: MD Anderson Cancer Center
John M. Koomen: H. Lee Moffitt Cancer Center & Research Institute
Jennifer A. Wargo: MD Anderson Cancer Center
Jane L. Messina: H. Lee Moffitt Cancer Center & Research Institute
Jianfei Qi: University of Maryland School of Medicine
Eric K. Lau: H. Lee Moffitt Cancer Center & Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Melanoma incidence and mortality rates are historically higher for men than women. Although emerging studies have highlighted tumorigenic roles for the male sex hormone androgen and its receptor (AR) in melanoma, cellular and molecular mechanisms underlying these sex-associated discrepancies are poorly defined. Here, we delineate a previously undisclosed mechanism by which androgen-activated AR transcriptionally upregulates fucosyltransferase 4 (FUT4) expression, which drives melanoma invasiveness by interfering with adherens junctions (AJs). Global phosphoproteomic and fucoproteomic profiling, coupled with in vitro and in vivo functional validation, further reveal that AR-induced FUT4 fucosylates L1 cell adhesion molecule (L1CAM), which is required for FUT4-increased metastatic capacity. Tumor microarray and gene expression analyses demonstrate that AR-FUT4-L1CAM-AJs signaling correlates with pathological staging in melanoma patients. By delineating key androgen-triggered signaling that enhances metastatic aggressiveness, our findings help explain sex-associated clinical outcome disparities and highlight AR/FUT4 and its effectors as potential prognostic biomarkers and therapeutic targets in melanoma.

Date: 2024
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DOI: 10.1038/s41467-024-45324-w

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