Androgen Drives Melanoma Invasiveness and Metastatic Spread by Inducing Tumorigenic Fucosylation

Authors

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
Eric K Lau

Publication Date

2-7-2024

Journal

Nature Communications

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.

Keywords

Humans, Male, Female, Melanoma, Androgens, Neural Cell Adhesion Molecule L1, Lewis X Antigen, Glycosylation, Receptors, Androgen, Cell Line, Tumor, Fucosyltransferases

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Associated Data

PMID: 38326303