<i>GGT6</i> as a Prognostic Biomarker and Therapeutic Target in Melanoma Using an Information-theoretical Method

<h3>Abstract</h3> <h3>Background/Aim:</h3> Melanoma is an aggressive malignancy with rising global incidence. While early surgical intervention improves survival in localized cases, treatment resistance and recurrence remain a challenge. This underscores the critical need to identify prognostic biomarkers for early diagnosis, personalized treatment, and novel therapeutic development. <h3>Materials and Methods:</h3> The GSE126076 and melanoma dataset (Skin Cutaneous Melanoma, TCGA, PanCancer Atlas) were analyzed using an information-theoretical method to identify prognostic factors. Survival analysis was performed via Kaplan-Meier curves and log-rank tests to compare high- and low-mRNA expression groups. <i>In vitro</i>, A375 cells and A2058 cells were treated with the GGT inhibitor 6-diazo-5-oxo-L-norleucin (DON). Cell viability was assessed using the CCK-8 assay and intracellular GSH levels were measured following treatment. <h3>Results:</h3> Through information-theoretic analysis and survival analysis, we identified <i>GGT6</i> as a prognostic gene in melanoma. Survival analysis revealed that high <i>GGT6</i> expression was significantly associated with shorter disease-specific survival across all disease stages. <i>In vitro</i>, 10 μM DON for 72 h reduced A375 cell proliferation by 90.72% versus control (<i>p</i>&lt;0.0001), with an IC₅₀ of 5.14 μM; and reduced A2058 cell proliferation by 60.93% (<i>p</i>&lt;0.0001), with an IC₅₀ of 7.93 μM. Measurement of GSH levels of A375 and A2058 cells revealed that melanoma cells treated with 10 μM DON exhibited lower GSH levels compared with the respective control groups (<i>p</i>&lt;0.0001 and <i>p</i>=0.0042, respectively). <h3>Conclusion:</h3> Our study is the first to demonstrate the association between <i>GGT6</i> expression levels and melanoma prognosis, and reveals that GGT inhibition suppresses melanoma cell viability. These findings provide new insights into the mechanisms of melanoma development and progression, and suggest GGT as a potential therapeutic target for clinical treatment.