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Androgen receptor signaling found to upregulate gene driving melanoma severity in men

In a recent study published by Nature Communications, researchers uncovered a previously unknown method by which androgen-activated androgen receptors (ARs) increase fucosyltransferase 4 (FUT4) expression, which promotes melanoma invasiveness by interfering with adherens junctions (AJs).



Study: Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation. Image Credit: Image Point Fr/Shutterstock.com

Background

Melanoma incidence and death rates are higher in males than in females, and sex hormones play an important role within the disease’s biology and progression. Studies have demonstrated that androgen and its receptor have tumorigenic functions in melanoma, although the underlying processes are poorly understood.

Men with advanced melanoma typically have lower clinical outcomes. Sex hormones, corresponding to G protein-coupled estrogen receptor (GPER) signaling, inhibit tumor development and boost anti-programmed death cell death 1 (anti-PD-1) immune checkpoint blockade effectiveness in a female mouse model.

Global fucosylation disrupts as melanoma progresses, affecting cell motility and ribonucleic acid (RNA) processing.

In regards to the study

In the current study, researchers investigated ways through which sex-hormone-regulated fucosylation results in disparately poor outcomes in male melanoma patients.

The researchers investigated the results of androgen-induced and transcriptionally energetic androgen receptors on melanoma biology and tumorigenicity. They focused on the AR-FUT4 signaling pathway and its role in male sex-related biological consequences in melanoma.

They confirmed the presence of a putative androgen response element (ARE) within the FUT4 5′-promoter region and created mutant promoter constructs.

The researchers further confirmed the androgen receptor-fucosyltransferase-4 axis modulation of cell signaling pathways in melanoma by creating empty vector (EV) controls or fucosyltransferase 4-overexpressing (FUT4-OE) melanoma cells.

They conducted phosphoproteomic profiling of empty vectors and Ari-treated or untreated FUT4-overexpressing cells, followed by multiple-stage comparative evaluation. The study sought to know how ARs regulate fucosylation machinery genes and their significance in melanoma biology.

The team discovered 368 distinct proteins (denoted by 484 phosphopeptide proteins) that were decreased by ≥2.0-fold in ARi-treated empty vector-WM793 cells (ARi-reduced phosphopeptide proteins).

They then classified the phosphopeptides as people who FUT4 overexpression could restore (AR-FUT4-based effector molecules, n=95) and people unrestored by fucosyltransferase-4  overexpression (“AR-based, FUT4-independent effector molecules, n=241).

The researchers performed further ingenuity pathway evaluation (IPA) on 141 androgen receptor-fucosyltransferase-4 axis down- or upregulated signatures in WM1366 and WM793 cells.

They measured the contacts between β-catenin, N-cadherin, and δ1-catenin, primary cytoplasmic adherens junction interactors. They performed proliferation and motility experiments to verify the phosphoproteomic results and determine the effect of AR-FUT4-AJ signaling on melanoma biology.

The team also investigated whether FUT8 contributes to the motility effects brought on by FUT4. In addition they assessed AR expression and its relationships with downstream effectors in human melanoma samples.

Results

Researchers uncovered a way by which androgen-activated androgen receptors increase FUT4 expression, which promotes melanoma invasiveness by interacting with AJs. FUT4 is a critical transcriptional goal of AR, disrupting cell-cell adhesion complexes in melanoma.

AR-FUT4-mediated melanoma metastasis requires L1CAM, a downstream effector fucosylated by FUT4.  Tumor microarray and gene expression evaluation revealed that AR-FUT4-L1CAM-AJs signaling is related to clinical staging in melanoma patients.

The researchers found that sex hormone-regulated fucosylation results in the poor outcomes seen in male melanoma patients.

The mechanism shows that androgen or its receptor signaling influences melanoma malignancy by increasing invasive and metastatic potential through tumorigenic fucosylation.

Androgen/AR regulates cellular fucosylation in melanoma, with AR binding sites present in 4 genes (FUT4, FUT1, SLC35C2, and FUK). Androgen stimulation causes FUK to downregulate while FUT4 upregulates, indicating that AR modulates FUK and FUT4 expression in melanoma cells.

The researchers discovered that 2FF and FUT4-OE reduce and promote melanoma cell motility, but ectopic FUT4 expression restores ARi-suppressed invasive potential. FUT4 levels are higher in metastatic lesions than in original melanoma tissues.

They identified L1CAM as a vital goal for the AR-FUT4 axis-induced melanoma invasiveness. FUT4-overexpressing cell lines produced more fucosylated proteins than FUT4-knockdown cell lines.

DHT stimulation significantly elevated the fucosylation of L1CAM, and knockdown or overexpression of FUT4 resulted in lower or higher cellular levels of fucosylated L1CAM. L1CAM deletion inhibited DHT- or FUT4-induced melanoma motility.

AR levels were higher in metastatic tumors from male patients, as was activated AR. Single-cell segmentation evaluation revealed that metastatic lesions included fewer activated AR-high cells than initial tumors, demonstrating AR’s tumor-promoting involvement, particularly in male melanoma patients.

Conclusion

The study findings showed that androgen-triggered signaling is critical in melanoma, specifically targeting AR/FUT4 and its effectors.

It supports the usage of AR antagonists to treat melanomas and advises employing androgen- and fucosylation-based indicators to stratify therapy.

AR activation enhances tumorigenic FUT4, leading to worse clinical outcomes in male patients. The work also relates the AR transcriptional repertoire to oncogenic protein fucosylation, which promotes melanoma invasiveness in androgen-responsive melanomas.

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