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

被引：30

作者：

Da Costa, Elodie M. ^{[1
,2
]}

Armaos, Gregory ^{[1
,2
]}

McInnes, Gabrielle ^{[1
,2
]}

Beaudry, Annie ^{[2
]}

Moquin-Beaudry, Gael ^{[1
,2
]}

Bertrand-Lehouillier, Virginie ^{[2
,3
]}

Caron, Maxime ^{[2
]}

Richer, Chantal ^{[2
]}

St-Onge, Pascal ^{[2
]}

Johnson, Jeffrey R. ^{[4
]}

Krogan, Nevan ^{[4
]}

Sai, Yuka ^{[5
]}

Downey, Michael ^{[5
]}

Rafei, Moutih ^{[1
,6
,7
]}

Boileau, Meaghan ^{[8
]}

Eppert, Kolja ^{[8
]}

Flores-Diaz, Ema ^{[9
]}

Haman, Andre ^{[9
]}

Hoang, Trang ^{[1
,9
]}

Sinnett, Daniel ^{[2
,10
]}

Beausejour, Christian ^{[1
,2
]}

McGraw, Serge ^{[2
,3
,11
]}

Raynal, Noel J. -M. ^{[1
,2
]}

机构：

[1] Univ Montreal, Dept Pharmacol & Physiol, Montreal, PQ, Canada

[2] St Justine Univ Hosp Res Ctr 7 17 020, 3175 Chemin Cote St Catherine, Montreal, PQ H3T 1C5, Canada

[3] Univ Montreal, Dept Biochim & Biol Mol, Montreal, PQ, Canada

[4] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA

[5] Ottawa Inst Syst Biol, Dept Cellular & Mol Med, Ottawa, ON, Canada

[6] Univ Montreal, Dept Microbiol Infectiol & Immunol, Montreal, PQ, Canada

[7] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada

[8] McGill Univ, Dept Pediat, Montreal, PQ, Canada

[9] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ, Canada

[10] Univ Montreal, Dept Pediat, Montreal, PQ, Canada

[11] Univ Montreal, Dept Obstet Gynecol, Montreal, PQ, Canada

来源：

JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH | 2019年 / 38卷 / 1期

关键词：

Cardiac glycosides; Proscillaridin A; MYC; Leukemia; Lysine acetylation; Chromatin remodelling; Lysine acetyltransferase; Leukemia stem cells; C-MYC; SUPER-ENHANCERS; TRANSCRIPTION FACTORS; P300; ACETYLATION; CELL IDENTITY; HISTONE H3; ACETYLTRANSFERASES; IDENTIFICATION; INHIBITION; RESISTANCE;

D O I：

10.1186/s13046-019-1242-8

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

BackgroundCardiac 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.MethodsProscillaridin 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.ResultsAt 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.ConclusionOverall, these results strongly support the repurposing of proscillaridin A in MYC overexpressing leukemia.

引用

页数：14

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