2. Academic Validation
  3. Ablation of Proton/Glucose Exporter SLC45A2 Enhances Melanosomal Glycolysis to Inhibit Melanin Biosynthesis and Promote Melanoma Metastasis

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

  • J Invest Dermatol. 2022 Oct;142(10):2744-2755.e9. doi: 10.1016/j.jid.2022.04.008.
Ye Liu 1,  Wenna Chi 2,  Lei Tao 2,  Guoqiang Wang 1,  R N V Krishna Deepak 3,  Linlin Sheng 1,  Taiqi Chen 4,  Yaqian Feng 1,  Xizhi Cao 1,  Lili Cheng 1,  Xinbin Zhao 1,  Xiaohui Liu 5,  Haiteng Deng 5,  Hao Fan 3,  Peng Jiang 4,  Ligong Chen 6
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China.
  • 2 School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China; Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
  • 3 Bioinformatics Institute (BII), Agency for Science, Technology and Research (A(∗)STAR), Singapore, Singapore.
  • 4 School of Life Sciences, Tsinghua University, Beijing, China.
  • 5 National Center for Protein Science, School of Life Sciences, Tsinghua University, Beijing, China.
  • 6 School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China; Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China. Electronic address: ligongchen@tsinghua.edu.cn.
PMID: 35469906 DOI: 10.1016/j.jid.2022.04.008
Abstract

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 mediates melanin synthesis and melanoma metastasis primarily by modulating melanosomal glucose metabolism.

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