A Histone Deacetylase Inhibitor Induces Acetyl-CoA Depletion Leading to Lethal Metabolic Stress in RAS-Pathway Activated Cells

Agnes Basseville; Pierre-Christian Violet; Maryam Safari; Carole Sourbier; W Marston Linehan; Robert W Robey; Mark Levine; Dan L Sackett; Susan E Bates

doi:10.3390/cancers14112643

A Histone Deacetylase Inhibitor Induces Acetyl-CoA Depletion Leading to Lethal Metabolic Stress in RAS-Pathway Activated Cells

Cancers (Basel). 2022 May 26;14(11):2643. doi: 10.3390/cancers14112643.

Authors

Agnes Basseville^{1

2}, Pierre-Christian Violet³, Maryam Safari⁴, Carole Sourbier^{5

6}, W Marston Linehan⁵, Robert W Robey^{1

7}, Mark Levine³, Dan L Sackett⁸, Susan E Bates^{1

4

9}

Affiliations

¹ Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
² Omics Data Science Unit, Institut de Cancérologie de l'Ouest, 49055 Angers, France.
³ Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ Division of Hematology/Oncology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
⁵ Urology Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20903, USA.
⁷ Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁸ Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
⁹ Hematology/Oncology Research Department, James J. Peters Department of Veterans Affairs Medical Center, New York, NY 10468, USA.

Abstract

Background: The mechanism of action of romidepsin and other histone deacetylase inhibitors is still not fully explained. Our goal was to gain a mechanistic understanding of the RAS-linked phenotype associated with romidepsin sensitivity.

Methods: The NCI60 dataset was screened for molecular clues to romidepsin sensitivity. Histone acetylation, DNA damage, ROS production, metabolic state (real-time measurement and metabolomics), and gene expression alterations (transcriptomics) were determined in KRAS-WT versus KRAS-mutant cell groups. The search for biomarkers in response to HDACi was implemented by supervised machine learning analysis on a 608-cell transcriptomic dataset and validated in a clinical dataset.

Results: Romidepsin treatment induced depletion in acetyl-CoA in all tested cell lines, which led to oxidative stress, metabolic stress, and increased death-particularly in KRAS-mutant cell lines. Romidepsin-induced stresses and death were rescued by acetyl-CoA replenishment. Two acetyl-CoA gene expression signatures associated with HDACi sensitivity were derived from machine learning analysis in the CCLE (Cancer Cell Line Encyclopedia) cell panel. Signatures were then validated in the training cohort for seven HDACi, and in an independent 13-patient cohort treated with belinostat.

Conclusions: Our study reveals the importance of acetyl-CoA metabolism in HDAC sensitivity, and it highlights acetyl-CoA generation pathways as potential targets to combine with HDACi.

Keywords: HDAC inhibitors; RAS; acetyl-CoA metabolism.

Abstract

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