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

Treg Grubb1, Pooneh Koochaki1, Sayed Matar2

  • 1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Nature Communications
|November 14, 2025
PubMed

Insights

Clear cell renal cell carcinoma (ccRCC) relies on the SLC1A1 transporter for growth. Targeting SLC1A1 disrupts cancer metabolism, hindering tumor progression and metastasis in ccRCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Pathways

Background:

  • Epigenetic alterations, specifically Histone H3 lysine 27 acetylation (H3K27ac) accumulation, characterize pVHL-deficient clear cell Renal Cell Carcinomas (ccRCCs).
  • Understanding metabolic dependencies in ccRCC is crucial for developing targeted therapies.

Purpose of the Study:

  • To identify metabolic dependencies in ccRCC.
  • To investigate the role of SLC1A1 in ccRCC pathogenesis.
  • To explore SLC1A1 as a therapeutic target.

Main Methods:

  • In vivo positive selection ORF screen in pVHL-proficient cells.
  • Mechanistic studies in pVHL-deficient cells.
  • Genetic and pharmacological inactivation of SLC1A1.
  • Analysis of human tumor data.
  • Evaluation in ccRCC animal models.

Main Results:

  • SLC1A1 (aspartate and glutamate transporter) is a metabolic dependency in ccRCC.
  • pVHL loss upregulates SLC1A1 independently of HIF via H3K27ac dysregulation.
  • SLC1A1 inactivation impairs ccRCC growth by depleting Asp/Glu metabolites.
  • SLC1A1 inhibition sensitizes ccRCC to anti-metabolite drugs.
  • High SLC1A1 expression correlates with reduced immune infiltration, oncogenic metabolism, and advanced disease.
  • SLC1A1 inactivation reduces lung metastasis and renal tumor outgrowth in vivo.

Conclusions:

  • SLC1A1 is a HIF-independent metabolic vulnerability in pVHL-deficient ccRCC.
  • Targeting SLC1A1 offers a promising therapeutic strategy for ccRCC.
  • SLC1A1 inactivation impacts tumor growth, metastasis, and drug sensitivity.

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