ArticleThe Journal of clinical investigation2024
HIF-2α expression and metabolic signaling require ACSS2 in clear cell renal cell carcinoma.
Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Targeting p300/CBP destabilizes HIF-2α and suppresses tumor growth in cell and animal models of clear cell renal cell carcinoma.Cancer letters · 2026Article
- ReducedTranslational andrology and urology · 2026Article
- Recent advances in etiology and treatment of von Hippel-Lindau Disease (VHLD).Cancer metastasis reviews · 2026Review
- Acetyl-coenzyme A synthetase 2-mediated acetyl-coenzyme A accumulation promotes mitophagy and tumor growth via increased H3K27ac in hepatitis B virus-related hepatocellular carcinoma.Clinical and molecular hepatology · 2026Article
- USP10 regulates HIF2α stability by deubiquitinating HIF2α regardless ofTranslational andrology and urology · 2026Article
- Acetate Metabolism in Thyroid Cancer Progression.International journal of molecular sciences · 2026Article
- MUL1 suppresses cervical cancer progression by targeting FUNDC1 for ubiquitination and inhibiting DRP1-dependent mitophagy.Journal of molecular histology · 2026Article
- Hallmarks of nuclear metabolism: implications for genome integrity, nuclear signaling, and therapeutic targeting.npj metabolic health and disease · 2026Review
- Tumor microenvironment-driven drug resistance in urologic cancers: mechanisms and therapeutic targets.Genes & genomics · 2026Review
- Editorial: Unraveling renal cell carcinoma: pathogenesis, therapeutic strategies, and future perspectives.Frontiers in medicine · 2026Article
- ACSS2 promotes proliferation and invasiveness of SKOV-3 and PA-1 ovarian cancer cell lines under hypoxia.Journal of ovarian research · 2025Article
- Renal cell carcinoma organoids for precision medicine: bridging the gap between models and patients.Journal of translational medicine · 2025Review
- Lipid reprogramming and ferroptosis crosstalk in clear cell renal cell carcinoma: metabolic vulnerabilities and therapeutic targeting.Molecular cancer · 2025Review
- KRAS G12V mutation-selective requirement for ACSS2 in colorectal adenoma formation.Cell reports · 2025Article
- CRABP2 promotes metastasis and lipid droplet accumulation in non-small cell lung cancer by downregulating PLAAT4.Journal of Cancer · 2025Article
- HIF-2α inhibitors in clear cell renal cell carcinoma: a clinical pharmacy perspective on lipid metabolism, therapeutic management, and resistance strategies.Frontiers in medicine · 2025Review
- ACSS1-dependent acetate utilization rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis.Cell reports · 2024Article
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2α signaling. Identifying means to regulate HIF-2α thus has potential therapeutic benefit. Acetyl-CoA synthetase 2 (ACSS2) converts acetate to acetyl-CoA and is associated with poor patient prognosis in ccRCC. Here we tested the effects of ACSS2 on HIF-2α and cancer cell metabolism and growth in ccRCC models and clinical samples. ACSS2 inhibition reduced HIF-2α levels and suppressed ccRCC cell line growth in vitro, in vivo, and in cultures of primary ccRCC patient tumors. This treatment reduced glycolytic signaling, cholesterol metabolism, and mitochondrial integrity, all of which are consistent with loss of HIF-2α. Mechanistically, ACSS2 inhibition decreased chromatin accessibility and HIF-2α expression and stability. While HIF-2α protein levels are widely regulated through pVHL-dependent proteolytic degradation, we identify a potential pVHL-independent pathway of degradation via the E3 ligase MUL1. We show that MUL1 can directly interact with HIF-2α and that overexpression of MUL1 decreased HIF-2α levels in a manner partially dependent on ACSS2. These findings identify multiple mechanisms to regulate HIF-2α stability and ACSS2 inhibition as a strategy to complement HIF-2α-targeted therapies and deplete pathogenically stabilized HIF-2α.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.