Journal Article

The SLC1A1/EAAT3 dicarboxylic amino acid transporter is an epigenetically dysregulated nutrient carrier that sustains oncogenic metabolic programs

Grubb, Treg, Coker, Jesse A., Hakimi, A. Ari, Chakraborty, Abhishek A., Choueiri, Toni K., Reznik, Eduard, Dubasik, Noah, Machaalani, Marc, Guenther, Matthew G., Parajuli, Gyanu, Asara, John M., Ghandour, Fatme, Tang, Cerise, Matar, Sayed, Koochaki, Pooneh, Chan, Timothy A., Signoretti, Sabina, Martinez, Steven R., Kaelin, William G., Saad, Eddy, Orlando, David A., Srivastava, Raghvendra M., Kotecha, Ritesh R., Khatun, Jesminara, Salem, Carleigh, Vanharanta, Sakari, Stauffer, Shaun R.

2025

Overview

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. Clear cell renal cell carcinoma (ccRCC) bears the hallmark loss of VHL but remains incurable. Here, the authors identify the SLC1A1 dicarboxylic amino acid transporter as an actionable, oncogenic, HIF-independent, metabolic dependency in VHL-deficient ccRCCs.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 38/15 / 38/5 / 38/90 / 49/47 / 49/91 / 631/67/2327 / 631/67/395 / 631/67/68 / 82/80 / Acetylation / Amino acids / Animal diseases / Animal models / Animals / Aspartic Acid - metabolism / Bar codes / Carcinoma, Renal Cell - genetics / Carcinoma, Renal Cell - metabolism / Carcinoma, Renal Cell - pathology / Cell Line, Tumor / Clear cell-type renal cell carcinoma / Cloning / Deactivation / Epigenesis, Genetic / Epigenetics / Excitatory Amino Acid Transporter 3 - genetics / Excitatory Amino Acid Transporter 3 - metabolism / Excitatory amino acid transporters / Gene Expression Regulation, Neoplastic / Genes / Genomics / Glutamic Acid - metabolism / Glutaminase / Histone H3 / Histones / Histones - metabolism / Humanities and Social Sciences / Humans / Hypoxia / Immunosuppressive agents / Intermediates / Kidney Neoplasms - genetics / Kidney Neoplasms - metabolism / Kidney Neoplasms - pathology / Lung Neoplasms - genetics / Lung Neoplasms - secondary / Lysine / Metabolites / Metastases / Metastasis / Mice / multidisciplinary / Nucleotides / Positive selection / Science / Science (multidisciplinary) / Tricarboxylic acid cycle / Tumors