ArticlePLoS genetics2015
ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate.
Article in PLoS genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
32 citing papers in PubMed, 45 citations in OpenAlex.
- Metabolomic effects of androgen deprivation therapy treatment for prostate cancer.Cancer medicine · 2020Trial
- Article
- Glucose Metabolism and Tumor Microenvironment: Mechanistic Insights and Therapeutic Implications.International journal of molecular sciences · 2025Review
- Crosstalk between metabolism and cell death in tumorigenesis.Molecular cancer · 2024Review
- Evolving landscape of PD-L2: bring new light to checkpoint immunotherapy.British journal of cancer · 2023Review
- Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions.Signal transduction and targeted therapy · 2023Review
- Bcl-xL Enforces a Slow-Cycling State Necessary for Survival in the Nutrient-Deprived Microenvironment of Pancreatic Cancer.Cancer research · 2022Article
- MESH1 knockdown triggers proliferation arrest through TAZ repression.Cell death & disease · 2022Article
- Potential Involvement ofCancers · 2022Article
- Genetics Responses to Hypoxia and Reoxygenation Stress inAnimals : an open access journal from MDPI · 2021Article
- E26 transformation-specific variant 4 as a tumor promotor in human cancers through specific molecular mechanisms.Molecular therapy oncolytics · 2021Review
- The regulation of ferroptosis by MESH1 through the activation of the integrative stress response.Cell death & disease · 2021Article
- All-trans retinoic acid reverses malignant biological behavior of hepatocarcinoma cells by regulating miR-200 family members.Genes & diseases · 2021Article
- Regulation of ferroptosis in cancer cells by YAP/TAZ and Hippo pathways: The therapeutic implications.Genes & diseases · 2021Review
- Ferroptosis of epithelial ovarian cancer: genetic determinants and therapeutic potential.Oncotarget · 2020Article
- PTBP3 promotes malignancy and hypoxia-induced chemoresistance in pancreatic cancer cells by ATG12 up-regulation.Journal of cellular and molecular medicine · 2020Article
- The vital role of ATP citrate lyase in chronic diseases.Journal of molecular medicine (Berlin, Germany) · 2020Review
- Function and regulation of the PEA3 subfamily of ETS transcription factors in cancer.American journal of cancer research · 2020Review
- Article
- Exome sequencing in 51 early onset non-familial CRC cases.Molecular genetics & genomic medicine · 2019Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis. Additionally, the loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while α-ketoglutarate levels decrease under hypoxia in control cells, α-ketoglutarate is paradoxically increased under hypoxia when ACC1 or ACLY are depleted. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4, likely via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased α-ketoglutarate. These results reveal that the ACC1/ACLY-α-ketoglutarate-ETV4 axis is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future.
Indexed as
Identifiers
What OpenQuestion holds
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.