title: ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate.
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.
authors.affiliation: 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.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Keenan
authors.affiliation: 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.
authors.forename: Beiyu
authors.initials: B
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Jianli
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Electrical and Computer Engineering, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Derek
authors.initials: D
authors.lastname: Cyr
authors.affiliation: 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.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.affiliation: 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.
authors.forename: Olga
authors.initials: O
authors.lastname: Ilkayeva
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Tollini
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Murphy
authors.affiliation: Department of Electrical and Computer Engineering, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lucas
authors.affiliation: 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.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: So Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Jen-Tsan
authors.initials: JT
authors.lastname: Chi
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors / Q000235:genetics*; D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism / Q000494:pharmacology; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D017500:Adenovirus E1A Proteins; C079853:ETV4 protein, human; D007656:Ketoglutaric Acids; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D001275:ATP Citrate (pro-S)-Lyase; C000588423:ACACA protein, human; D000103:Acetyl-CoA Carboxylase