MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival
- Matthew Hurd1,7,
- Jeffrey Pino1,7,
- Kay Jang1,
- Michael M. Allevato1,
- Marina Vorontchikhina1,
- Wataru Ichikawa1,
- Yifan Zhao1,
- Ryan Gates1,
- Emily Villalpando1,
- Michael J. Hamilton1,
- Francesco Faiola1,
- Songqin Pan2,3,
- Yue Qi4,
- Yu-Wen Hung4,5,
- Thomas Girke2,3,
- David Ann4,5,
- Victoria Seewaldt5,6 and
- Ernest Martinez1,2
- 1Department of Biochemistry, University of California Riverside, Riverside, California 92521, USA;
- 2Institute for Integrative Genome Biology, University of California Riverside, Riverside, California 92521, USA;
- 3Department of Botany and Plant Sciences, University of California Riverside, Riverside, California 92521, USA;
- 4Department of Diabetes Complications and Metabolism, Beckman Research Institute, Comprehensive Cancer Center, City of Hope, Duarte, California 91010, USA;
- 5Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, Comprehensive Cancer Center, City of Hope, Duarte, California 91010, USA;
- 6Department of Population Sciences, Beckman Research Institute, Comprehensive Cancer Center, City of Hope, Duarte, California 91010, USA
- Corresponding author: ernest.martinez{at}ucr.edu
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↵7 These authors contributed equally to this work.
Abstract
The MYC oncogenic transcription factor is acetylated by the p300 and GCN5 histone acetyltransferases. The significance of MYC acetylation and the functions of specific acetylated lysine (AcK) residues have remained unclear. Here, we show that the major p300-acetylated K148(149) and K157(158) sites in human (or mouse) MYC and the main GCN5-acetylated K323 residue are reversibly acetylated in various malignant and nonmalignant cells. Oncogenic overexpression of MYC enhances its acetylation and alters the regulation of site-specific acetylation by proteasome and deacetylase inhibitors. Acetylation of MYC at different K residues differentially affects its stability in a cell type-dependent manner. Lysine-to-arginine substitutions indicate that although none of the AcK residues is required for MYC stimulation of adherent cell proliferation, individual AcK sites have gene-specific functions controlling select MYC-regulated processes in cell adhesion, contact inhibition, apoptosis, and/or metabolism and are required for the malignant cell transformation activity of MYC. Each AcK site is required for anchorage-independent growth of MYC-overexpressing cells in vitro, and both the AcK148(149) and AcK157(158) residues are also important for the tumorigenic activity of MYC transformed cells in vivo. The MYC AcK site-specific signaling pathways identified may offer new avenues for selective therapeutic targeting of MYC oncogenic activities.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.350736.123.
- Received April 19, 2023.
- Accepted October 2, 2023.
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