The SLC1A1/EAAT3 dicarboxylic amino acid transporter is an epigenetically dysregulated nutrient carrier that sustains oncogenic metabolic programs
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.
Authors
- Eddy Saad (ORCID: https://orcid.org/0000-0001-8700-9312)
- Shaun R. Stauffer (ORCID: https://orcid.org/0000-0002-6332-1827)
- Matthew G. Guenther (ORCID: https://orcid.org/0009-0006-6779-1195)
- Ritesh R. Kotecha (ORCID: https://orcid.org/0000-0002-0223-3479)
- Steven R. Martinez
- Sayed Matar (ORCID: https://orcid.org/0000-0002-9687-2318)
- John M. Asara (ORCID: https://orcid.org/0000-0001-7450-2589)
- Abhishek A. Chakraborty (ORCID: https://orcid.org/0000-0002-3382-188X)
- Sabina Signoretti (ORCID: https://orcid.org/0000-0002-5000-9105)
- Toni K. Choueiri (ORCID: https://orcid.org/0000-0002-9201-3217)
- Jesminara Khatun (ORCID: https://orcid.org/0000-0002-2949-2198)
- Treg Grubb (ORCID: https://orcid.org/0000-0002-3388-758X)
- Marc Machaalani (ORCID: https://orcid.org/0000-0002-6708-9922)
- Sakari Vanharanta (ORCID: https://orcid.org/0000-0001-5619-7963)
- Pooneh Koochaki
- Timothy A. Chan (ORCID: https://orcid.org/0000-0002-9265-0283)
- Ed Reznik (ORCID: https://orcid.org/0000-0002-6511-5947)
- Jesse A. Coker (ORCID: https://orcid.org/0000-0003-1842-9860)
- William G. Kaelin (ORCID: https://orcid.org/0000-0002-0574-4856)
- A. Ari Hakimi (ORCID: https://orcid.org/0000-0002-0930-8824)
- Noah Dubasik
- David Orlando (ORCID: https://orcid.org/0009-0007-2170-0208)
- Cerise Tang
- Raghvendra M. Srivastava
- Carleigh Salem
- Fatme Ghandour (ORCID: https://orcid.org/0000-0002-4091-0063)
- Gyanu Parajuli
Institutions
- Brigham and Women's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Cleveland Clinic (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Helsinki (FI)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Cleveland Clinic Lerner College of Medicine (US)
- AVEO Oncology (United States) (US)
- Dana-Farber Cancer Institute (US)
- Dana-Farber Brigham Cancer Center (US)
- Case Western Reserve University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-14
- DOI
- https://doi.org/10.1038/s41467-025-64983-x
- Citations
- 1
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.94