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

Treg Grubb, Pooneh Koochaki, Sayed Matar, Fatme Ghandour, Marc Machaalani, Eddy Saad, Cerise Tang, Eduard Reznik, Jesminara Khatun, Carleigh Salem, Noah Dubasik, David A. Orlando, Matthew G. Guenther, Gyanu Parajuli, Raghvendra M. Srivastava, Steven R. Martinez, Jesse A. Coker, Ritesh R. Kotecha, A. Ari Hakimi, John M. Asara, Timothy A. Chan, Sakari Vanharanta, Shaun R. Stauffer, William G. Kaelin, Sabina Signoretti, Toni K. Choueiri and Abhishek A. Chakraborty ()
Additional contact information
Treg Grubb: Cleveland Clinic
Pooneh Koochaki: Cleveland Clinic
Sayed Matar: Brigham and Women’s Hospital
Fatme Ghandour: Brigham and Women’s Hospital
Marc Machaalani: Harvard Medical School
Eddy Saad: Harvard Medical School
Cerise Tang: Memorial Sloan Kettering Cancer Center
Eduard Reznik: Memorial Sloan Kettering Cancer Center
Jesminara Khatun: Cleveland Clinic
Carleigh Salem: Cleveland Clinic
Noah Dubasik: Cleveland Clinic
David A. Orlando: Syros Pharmaceuticals Inc.
Matthew G. Guenther: Syros Pharmaceuticals Inc.
Gyanu Parajuli: Cleveland Clinic
Raghvendra M. Srivastava: Cleveland Clinic
Steven R. Martinez: Cleveland Clinic
Jesse A. Coker: Cleveland Clinic
Ritesh R. Kotecha: Memorial Sloan Kettering Cancer Center
A. Ari Hakimi: Memorial Sloan Kettering Cancer Center
John M. Asara: Harvard Medical School
Timothy A. Chan: Cleveland Clinic
Sakari Vanharanta: University of Helsinki
Shaun R. Stauffer: Cleveland Clinic
William G. Kaelin: Harvard Medical School
Sabina Signoretti: Brigham and Women’s Hospital
Toni K. Choueiri: Harvard Medical School
Abhishek A. Chakraborty: Cleveland Clinic

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-64983-x

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