Ablation of Proton/Glucose Exporter SLC45A2 Enhances Melanosomal Glycolysis to Inhibit Melanin Biosynthesis and Promote Melanoma Metastasis

Sequence variation in SLC45A2 are responsible for oculocutaneous albinism type 4 in many species and are associated with melanoma susceptibility, but the molecular mechanism is unclear. In this study, we used Slc45a2-deficient melanocyte and mouse models to elucidate the roles of SLC45A2 in melanogenesis and melanoma metastasis. We found that the acidified cellular environment impairs the activity of key melanogenic enzyme tyrosinase in Slc45a2-deficient melanocytes. SLC45A2 is identified as a proton/glucose exporter in melanosomes, and its ablation increases the acidification of melanosomal pH through enhanced glycolysis. Intriguingly, 13C-glucose-labeled metabolic flux and biochemical assays show that melanosomes are active glucose-metabolizing organelles, indicating that elevated glycolysis mainly occurs in melanosomes owing to Slc45a2 deficiency. Moreover, Slc45a2 deficiency significantly upregulates the activities of glycolytic enzymes and phosphatidylinositol 3-kinase/protein kinase B signaling to promote glycolysis-dependent survival and metastasis of melanoma cells. Collectively, our study reveals that the proton/glucose exporter SLC45A2 me-diates melanin synthesis and melanoma metastasis primarily by modulating melanosomal glucose metabolism.

Automated summary

Sequence variation in SLC45A2 is associated with oculocutaneous albinism type 4 and melanoma susceptibility. The study reveals that SLC45A2 plays a critical role in melanogenesis and melanoma metastasis. Slc45a2-deficient melanocytes have impaired activity of the key melanogenic enzyme tyrosinase due to the acidified cellular environment. SLC45A2 is identified as a proton/glucose exporter in melanosomes, and its deficiency leads to increased acidification of melanosomal pH through enhanced glycolysis. Additionally, Slc45a2 deficiency upregulates glycolytic enzymes and PI3K/AKT signaling, promoting glycolysis-dependent survival and metastasis of melanoma cells.