Acetyl-CoA promotes glioblastoma cell adhesion and migration through Ca2+–NFAT signaling
- Joyce V. Lee1,2,
- Corbett T. Berry3,4,
- Karla Kim1,2,
- Payel Sen5,
- Taehyong Kim6,
- Alessandro Carrer1,2,
- Sophie Trefely1,2,7,
- Steven Zhao1,2,
- Sully Fernandez1,2,
- Lauren E. Barney8,
- Alyssa D. Schwartz8,
- Shelly R. Peyton8,
- Nathaniel W. Snyder7,
- Shelley L. Berger5,9,10,
- Bruce D. Freedman3 and
- Kathryn E. Wellen1,2
- 1Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
- 2Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
- 3Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 4School of Biomedical Engineering, Drexel University, Philadelphia, Pennsylvania 19104, USA;
- 5Penn Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
- 6Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
- 7A.J. Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania 19104, USA;
- 8Department of Chemical Engineering, University of Massachusetts-Amherst, Amherst, Massachusetts 01003, USA;
- 9Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 10Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
- Corresponding author: wellenk{at}upenn.edu
Abstract
The metabolite acetyl-coenzyme A (acetyl-CoA) is the required acetyl donor for lysine acetylation and thereby links metabolism, signaling, and epigenetics. Nutrient availability alters acetyl-CoA levels in cancer cells, correlating with changes in global histone acetylation and gene expression. However, the specific molecular mechanisms through which acetyl-CoA production impacts gene expression and its functional roles in promoting malignant phenotypes are poorly understood. Here, using histone H3 Lys27 acetylation (H3K27ac) ChIP-seq (chromatin immunoprecipitation [ChIP] coupled with next-generation sequencing) with normalization to an exogenous reference genome (ChIP-Rx), we found that changes in acetyl-CoA abundance trigger site-specific regulation of H3K27ac, correlating with gene expression as opposed to uniformly modulating this mark at all genes. Genes involved in integrin signaling and cell adhesion were identified as acetyl-CoA-responsive in glioblastoma cells, and we demonstrate that ATP citrate lyase (ACLY)-dependent acetyl-CoA production promotes cell migration and adhesion to the extracellular matrix. Mechanistically, the transcription factor NFAT1 (nuclear factor of activated T cells 1) was found to mediate acetyl-CoA-dependent gene regulation and cell adhesion. This occurs through modulation of Ca2+ signals, triggering NFAT1 nuclear translocation when acetyl-CoA is abundant. The findings of this study thus establish that acetyl-CoA impacts H3K27ac at specific loci, correlating with gene expression, and that expression of cell adhesion genes are driven by acetyl-CoA in part through activation of Ca2+–NFAT signaling.
Keywords
Footnotes
-
Supplemental material is available for this article.
-
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.311027.117.
- Received December 19, 2017.
- Accepted March 26, 2018.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.