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.

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Citation

Published Version (Please cite this version)

10.1371/journal.pgen.1005599

Publication Info

Keenan, Melissa M, Beiyu Liu, Xiaohu Tang, Jianli Wu, Derek Cyr, Robert D Stevens, Olga Ilkayeva, Zhiqing Huang, et al. (2015). ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate. PLoS Genet, 11(10). p. e1005599. 10.1371/journal.pgen.1005599 Retrieved from https://hdl.handle.net/10161/13614.

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Scholars@Duke

Stevens

Robert David Stevens

Adjunct Assistant Professor of Medicine
Ilkayeva

Olga Ilkayeva

Assistant Professor in Medicine

Olga Ilkayeva, Ph.D., is the Director of the Metabolomics Core Laboratory at Duke Molecular Physiology Institute. She received her Ph.D. training in Cell Regulation from UT Southwestern Medical Center at Dallas, TX. Her postdoctoral research in the laboratory of Dr. Chris Newgard at Duke University Medical Center focused on lipid metabolism and regulation of insulin secretion. As a research scientist at the Stedman Nutrition and Metabolism Center, Dr. Ilkayeva expanded her studies to include the development of targeted mass spectrometry analyses. Currently, she works on developing and validating quantitative mass spectrometry methods used for metabolic profiling of various biological models with emphasis on diabetes, obesity, cardiovascular disease, and the role of gut microbiome in both health and disease.

Huang

Zhiqing Huang

Assistant Professor in Obstetrics and Gynecology

Dr. Huang is an Assistant Professor in the Department of Obstetrics and Gynecology, Division of Reproductive Sciences, at Duke University Medical Center. She obtained her MD at North China Coal Medical University in China and her PhD at the University of Heidelberg in Germany under the mentorship of Dr. Ralph Witzgall. She did her postdoctoral training with Dr. Jiemin Wong at Baylor College of Medicine, studying how histone methylation and chromatin modifications regulate androgen receptor transcription. 

Dr. Huang’s research includes the following:

•The factors in the tumor microenvironment contribute to ovarian cancer progress;
•New drug development for recurrent ovarian cancer treatment;
•The early DNA methylation profiles contribute to cancer development in late life;
•The special changes in the tumor microenvironment;
•Epigenetics and epigenomics.
*The impact of lipid metabolism in the tumor microenvironment in cancer progression and treatment.
*Impact of ferroptosis in endometriosis development. 

Dr. Huang has received an R03 funding titled “Role of Age-Related Changes in the Tumor Microenvironment on Ovarian Cancer Progression” from NIA at NIH for 2021-2023.
Dr. Huang received Charles B. Hammond's Research Fund from the Department of Obstetrics and Gynecology at Duke University in November 2022, for a project titled "Single Cell Spatial Transcriptomics in Highly Aggressive and Less Aggressive Ovarian Cancer".
Dr. Huang has received Duke Cancer Institute 2023 spring pilot study award for07012023-06302024, the project title is "Age Effects on Chemotherapy Targeting Cells Causing Ovarian Cancer Recurrence”.
Dr. Huang has received the American Cancer Society -Duke Cancer Institute (ASC-DCI) 2024 spring pilot study award for 07012024-06302025. The project title is "Early Establishment of Epigenetic Profiles that Increase Cancer Risk in Late Life”.
Dr. Huang received Charles B. Hammond's Research Fund from the Department of Obstetrics and Gynecology at Duke University in November 2023 for 01012024-12312024. The project's title is "Age Effects on Chemotherapy Targeting Cells Causing Ovarian Cancer Recurrence".

Murphy

Susan Kay Murphy

Associate Professor in Obstetrics and Gynecology

Dr. Murphy is a tenured Associate Professor in the Department of Obstetrics and Gynecology and serves as Chief of the Division of Reproductive Sciences. As a molecular biologist with training in human epigenetics, her research interests are largely centered around the role of epigenetic modifications in health and disease. 

Dr. Murphy has ongoing projects on gynecologic malignancies, including approaches to eradicate ovarian cancer cells that survive chemotherapy and later give rise to recurrent disease. Dr. Murphy is actively involved in many collaborative projects relating to the Developmental Origins of Health and Disease (DOHaD).

Her lab is currently working on preconception environmental exposures in males, particularly on the impact of cannabis on the sperm epigenome and the potential heritability of these effects. They are also studying the epigenetic and health effects of in utero exposures, with primary focus on children from the Newborn Epigenetics STudy (NEST), a pregnancy cohort she co-founded who were recruited from central North Carolina between 2005 and 2011. Dr. Murphy and her colleagues continue to follow NEST children to determine relationships between prenatal exposures and later health outcomes.

Muoio

Deborah Marie Muoio

George Barth Geller Distinguished Professor of Cardiovascular Disease

Deb Muoio is professor in the Departments of Medicine and Pharmacology & Cancer Biology, George Barth Geller Distinguished Professor of Cardiovascular Disease, and Associate Director of the Duke Molecular Physiology Institute (DMPI). She is viewed nationally and internationally as a leader in the fields of diabetes, obesity, exercise physiology, and mitochondrial energy metabolism. Her laboratory investigates mechanisms of metabolic regulation, with emphasis on molecular events that link lifestyle factors such as over nutrition and physical inactivity to metabolic disorders, including obesity, diabetes, and heart failure. Her program features a translational approach that combines work in animal and cell-based models with human studies, using genetic engineering, molecular biology and mass spectrometry-based metabolomics and proteomics as tools to understand the interplay between mitochondrial physiology and cardiometabolic health. Her laboratory developed a sophisticated platform for deep and comprehensive assessment of mitochondrial bioenergetics and energy transduction. Her team is integrating this new platform with metabolomics, proteomics, and metabolic flux analysis to gain insights into mechanisms by which mitochondria modulate insulin action and metabolic resilience. She has published more than 120 papers in prominent journals such as Cell, Cell Metabolism, Circulation, Circulation Research, Diabetes, and JCI Insight. Dr. Muoio’s laboratory has enjoyed longstanding support from the NIDDK and NHLBI.

PhD, University of North Carolina, Chapel Hill, NC

Kim

So Young Kim

Associate Research Professor in Molecular Genetics and Microbiology

I serve as Director of the Duke Functional Genomics Core Facility, where our central mission is to provide resources for high-throughput analysis of gene function and small molecule screens for drug discovery. Our core works with Duke investigators to provide the expertise, infrastructure and libraries necessary for these screens and can collaborate on all stages of the screening project, including study design, assay optimization and data analysis. The facility also provides services for custom cell line engineering using techniques including CRISPR knockouts/knockins, RNAi gene suppression and ORF expression. Our lab is also interested in collaborating with investigators to develop and improve existing methodologies to enhance the utility of functional genomics tools within the lab. 

I am also the Director of the Duke Microbiome Core Facility, which supports the research of investigators seeking to uncover the roles that microbiomes play in human health and the environment. The core provides assistance with study design, sample management, DNA extractions, NGS library prep and data analysis. The lab is also interested in developing new techniques and analysis tools to better assess microbiome composition across a range of sample types.


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