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Heart failure drug proscillaridin A targets MYC overexpressing leukemia through global loss of lysine acetylation.

ABSTRACT: BACKGROUND:Cardiac glycosides are approved for the treatment of heart failure as Na+/K+ pump inhibitors. Their repurposing in oncology is currently investigated in preclinical and clinical studies. However, the identification of a specific cancer type defined by a molecular signature to design targeted clinical trials with cardiac glycosides remains to be characterized. Here, we demonstrate that cardiac glycoside proscillaridin A specifically targets MYC overexpressing leukemia cells and leukemia stem cells by causing MYC degradation, epigenetic reprogramming and leukemia differentiation through loss of lysine acetylation. METHODS:Proscillaridin A anticancer activity was investigated against a panel of human leukemia and solid tumor cell lines with different MYC expression levels, overexpression in vitro systems and leukemia stem cells. RNA-sequencing and differentiation studies were used to characterize transcriptional and phenotypic changes. Drug-induced epigenetic changes were studied by chromatin post-translational modification analysis, expression of chromatin regulators, chromatin immunoprecipitation, and mass-spectrometry. RESULTS:At a clinically relevant dose, proscillaridin A rapidly altered MYC protein half-life causing MYC degradation and growth inhibition. Transcriptomic profile of leukemic cells after treatment showed a downregulation of genes involved in MYC pathways, cell replication and an upregulation of hematopoietic differentiation genes. Functional studies confirmed cell cycle inhibition and the onset of leukemia differentiation even after drug removal. Proscillaridin A induced a significant loss of lysine acetylation in histone H3 (at lysine 9, 14, 18 and 27) and in non-histone proteins such as MYC itself, MYC target proteins, and a series of histone acetylation regulators. Global loss of acetylation correlated with the rapid downregulation of histone acetyltransferases. Importantly, proscillaridin A demonstrated anticancer activity against lymphoid and myeloid stem cell populations characterized by MYC overexpression. CONCLUSION:Overall, these results strongly support the repurposing of proscillaridin A in MYC overexpressing leukemia.

SUBMITTER: Da Costa EM

PROVIDER: S-EPMC6563382 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Heart failure drug proscillaridin A targets MYC overexpressing leukemia through global loss of lysine acetylation.

Da Costa Elodie M EM Armaos Gregory G McInnes Gabrielle G Beaudry Annie A Moquin-Beaudry Gaël G Bertrand-Lehouillier Virginie V Caron Maxime M Richer Chantal C St-Onge Pascal P Johnson Jeffrey R JR Krogan Nevan N Sai Yuka Y Downey Michael M Rafei Moutih M Boileau Meaghan M Eppert Kolja K Flores-Díaz Ema E Haman André A Hoang Trang T Sinnett Daniel D Beauséjour Christian C McGraw Serge S Raynal Noël J-M NJ

Journal of experimental & clinical cancer research : CR 20190613 1

<h4>Background</h4>Cardiac glycosides are approved for the treatment of heart failure as Na<sup>+</sup>/K<sup>+</sup> pump inhibitors. Their repurposing in oncology is currently investigated in preclinical and clinical studies. However, the identification of a specific cancer type defined by a molecular signature to design targeted clinical trials with cardiac glycosides remains to be characterized. Here, we demonstrate that cardiac glycoside proscillaridin A specifically targets MYC overexpress ...[more]

PMID: 31196146

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Project description:Lysine acetylation is thought to provide a mechanism for regulating metabolism in diverse bacteria. Indeed, many studies have shown that the majority of enzymes involved in central metabolism are acetylated and that acetylation can alter enzyme activity. However, the details regarding this regulatory mechanism are still unclear, specifically with regard to the signals that induce lysine acetylation. To better understand this global regulatory mechanism, we profiled changes in lysine acetylation during growth of Escherichia coli on the hexose glucose or the pentose xylose at both high and low sugar concentrations using label-free mass spectrometry. The goal was to see whether lysine acetylation differed during growth on these two different sugars. No significant differences, however, were observed. Rather, the initial sugar concentration was the principal factor governing changes in lysine acetylation, with higher sugar concentrations causing more acetylation. These results suggest that acetylation does not target specific metabolic pathways but rather simply targets accessible lysines, which may or may not alter enzyme activity. They further suggest that lysine acetylation principally results from conditions that favor accumulation of acetyl phosphate, the principal acetate donor in E. coliIMPORTANCE Bacteria alter their metabolism in response to nutrient availability, growth conditions, and environmental stresses using a number of different mechanisms. One is lysine acetylation, a posttranslational modification known to target many metabolic enzymes. However, little is known about this regulatory mode. We investigated the factors inducing changes in lysine acetylation by comparing growth on glucose and xylose. We found that the specific sugar used for growth did not alter the pattern of acetylation; rather, the amount of sugar did, with more sugar causing more acetylation. These results imply that lysine acetylation is a global regulatory mechanism that is responsive not to the specific carbon source per se but rather to the accumulation of downstream metabolites.

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Heart failure drug proscillaridin A targets MYC overexpressing leukemia through global loss of lysine acetylation.

Publications

Heart failure drug proscillaridin A targets MYC overexpressing leukemia through global loss of lysine acetylation.

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