ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate.
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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.
SubjectATP Citrate (pro-S)-Lyase
Adenovirus E1A Proteins
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Published Version (Please cite this version)10.1371/journal.pgen.1005599
Publication InfoChi, JT; Cyr, Derek; Huang, Z; Ilkayeva, Olga; Keenan, MM; Kim, So Young; ... Wu, J (2015). ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate. PLoS Genet, 11(10). pp. e1005599. 10.1371/journal.pgen.1005599. Retrieved from https://hdl.handle.net/10161/13614.
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Assistant Research Professor in Molecular Genetics and Microbiology
Associate Professor in Obstetrics and Gynecology
Ovarian and cervical cancer epigenetics, imprinted genes in ovarian and cervical cancers, identification of methylation biomarkers of disease, ovarian cancer stem cells, chemotherapeutic response in ovarian cancer, tumor dormancy, the influence of the in utero environment on DNA methylation and risk of disease.
Adjunct Assistant Professor of Medicine
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