1. Abstract 1381: Targeting histone acetyltransferases to reprogram high C-MYC expressing cancers
- Author
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Yuka Sai, Annie Beaudry, Gregory Armaos, Daniel Sinnett, Maxime Caron, Chantal Richer, Pascal St-Onge, Noël J.-M. Raynal, Serge McGraw, Michael Downey, Nevan J. Krogan, Jeffrey R. Johnson, and Elodie M. Da Costa
- Subjects
Histone Acetyltransferases ,Cancer Research ,biology ,Cellular differentiation ,Histone acetyltransferase ,Protein degradation ,Proscillaridin ,Chromatin ,Histone ,Oncology ,medicine ,biology.protein ,Cancer research ,Epigenetics ,medicine.drug - Abstract
In cancer, epigenetic modifications are strongly altered and are responsible for gene expression aberrations. In a drug screening initiative, we recently reported that proscillaridin, a cardiac glycoside (CG), exhibits unsuspected epigenetic and anticancer activities. To understand CG's epigenetic mechanisms of action, we performed RNA sequencing analysis, which showed proscillaridin effects on global gene expressions in acute lymphoblastic leukemia cells (MOLT-4). Genes associated with apoptosis and cell differentiation were upregulated whereas master transcription factors and oncogenic pathway genes were downregulated. Mechanistic studies revealed that proscillaridin decreased histone 3 acetylation, which correlated with histone acetyltransferase (KATs) downregulation (CBP, P300, TIP60, GCN5 and MOZ). Acetylome studies by mass spectrometry showed an acetylation loss in chromatin regulators, the oncogene C-MYC and its associated proteins. Proscillaridin induced C-MYC transcript and protein degradation. Moreover, in a panel of cancer cell lines, we measured that cancer cells sensitivity to proscillaridin treatment was positively correlated with C-MYC protein levels. Conversely, proscillaridin did not affect C-MYC protein level in low C-MYC expressing cancer cell lines. For the first time, we showed that CGs target histone acetyltransferases and C-MYC oncogene in high C-MYC expressing cancers. We propose that CGs can be repurposed as new epigenetic drugs in high C-MYC expressing cancers. Citation Format: Elodie M. Da Costa, Gregory Armaos, Annie Beaudry, Chantal Richer, Maxime Caron, Pascal St-Onge, Jeffrey Johnson, Nevan Krogan, Yuka Sai, Michael Downey, Daniel Sinnett, Serge McGraw, Noël J. Raynal. Targeting histone acetyltransferases to reprogram high C-MYC expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1381.
- Published
- 2018