Nature communications · 2025
The SLC1A1/EAAT3 dicarboxylic amino acid transporter is an epigenetically dysregulated nutrient carrier that sustains oncogenic metabolic programs.
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Grubb Treg, Koochaki Pooneh, Matar Sayed, Ghandour Fatme, Machaalani Marc, Saad Eddy, Tang Cerise, Reznik Eduard, Khatun Jesminara, Salem Carleigh, Dubasik Noah, Orlando David A, Guenther Matthew G, Parajuli Gyanu, Srivastava Raghvendra M, Martinez Steven R, Coker Jesse A, Kotecha Ritesh R, Hakimi A Ari, Asara John M, Chan Timothy A, Vanharanta Sakari, Stauffer Shaun R, Kaelin William G, Signoretti Sabina, Choueiri Toni K, Chakraborty Abhishek A
Аннотация
Epigenetic dysregulation, including accumulation of Histone H3 lysine 27 acetylation (H3K27ac), is a hallmark of pVHL-deficient clear cell Renal Cell Carcinomas (ccRCCs). Using an in vivo positive selection ORF screen in poorly tumorigenic pVHL-proficient cells and mechanistic studies in pVHL-deficient cells, we discovered that the aspartate (Asp) and glutamate (Glu) transporter, SLC1A1/EAAT3, is a metabolic dependency in ccRCC. pVHL loss promotes Hypoxia Inducible Factor (HIF)-independent SLC1A1 expression via H3K27ac dysregulation. SLC1A1 inactivation, genetically or pharmacologically, depletes Asp/Glu-derived metabolites (e.g., Tricarboxylic acid cycle and nucleotide intermediates), impedes ccRCC growth, and sensitizes ccRCCs to anti-metabolite drugs (e.g., glutaminase blockers). In human tumors, higher SLC1A1 expression is associated with reduced immune infiltration, oncogenic metabolic programs, and advanced stage/metastatic disease. Finally, in ccRCC animal models, SLC1A1 inactivation diminishes lung metastasis and the outgrowth of established renal tumors. Altogether, our studies credential SLC1A1 as an actionable, HIF-independent, metabolic dependency in pVHL-deficient ccRCCs.