ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate.

Autor:	Keenan MM; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, United States of America., Liu B; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, United States of America., Tang X; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, United States of America., Wu J; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, United States of America., Cyr D; Department of Electrical and Computer Engineering, Duke University Medical Center, Durham, North Carolina, United States of America., Stevens RD; Sarah W Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina, United States of America; Duke Institute of Molecular Physiology, Duke University Medical Center, Durham, North Carolina, United States of America., Ilkayeva O; Sarah W Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina, United States of America; Duke Institute of Molecular Physiology, Duke University Medical Center, Durham, North Carolina, United States of America., Huang Z; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina, United States of America., Tollini LA; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, United States of America., Murphy SK; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina, United States of America., Lucas J; Department of Electrical and Computer Engineering, Duke University Medical Center, Durham, North Carolina, United States of America., Muoio DM; Sarah W Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina, United States of America; Duke Institute of Molecular Physiology, Duke University Medical Center, Durham, North Carolina, United States of America., Kim SY; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America., Chi JT; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
Jazyk:	angličtina
Zdroj:	PLoS genetics [PLoS Genet] 2015 Oct 09; Vol. 11 (10), pp. e1005599. Date of Electronic Publication: 2015 Oct 09 (Print Publication: 2015).
DOI:	10.1371/journal.pgen.1005599
Abstrakt:	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.
Databáze:	MEDLINE
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