Heart Failure Drug Proscillaridin A Targets MYC Overexpressing Leukemia Through Global Loss of Lysine Acetylation

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2019 Jun 15

PMID 31196146

Citations 18

Authors

Elodie M Da Costa

Gregory Armaos

Gabrielle McInnes

Annie Beaudry

Gael Moquin-Beaudry

Virginie Bertrand-Lehouillier

Maxime Caron

Chantal Richer

Pascal St-Onge

Jeffrey R Johnson

Nevan Krogan

Yuka Sai

Michael Downey

Moutih Rafei

Meaghan Boileau

Kolja Eppert

Ema Flores-Diaz

Andre Haman

Trang Hoang

Daniel Sinnett

Christian Beausejour

Serge McGraw

Noel J-M Raynal

Affiliations

Soon will be listed here.

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.

Citing Articles

Semisupervised Contrastive Learning for Bioactivity Prediction Using Cell Painting Image Data.

Bushiri Pwesombo D, Beese C, Schmied C, Sun H J Chem Inf Model. 2025; 65(2):528-543.

PMID: 39761993 PMC: 11776044. DOI: 10.1021/acs.jcim.4c00835.

Cell Fate Dynamics Reconstruction Identifies TPT1 and PTPRZ1 Feedback Loops as Master Regulators of Differentiation in Pediatric Glioblastoma-Immune Cell Networks.

Uthamacumaran A Interdiscip Sci. 2024; 17(1):59-85.

PMID: 39420135 DOI: 10.1007/s12539-024-00657-4.

Identification and validation of CCL5 as a key gene in HIV infection and pulmonary arterial hypertension.

Yang M, Bi W, Zhang Z Front Cardiovasc Med. 2024; 11:1417701.

PMID: 39119185 PMC: 11306045. DOI: 10.3389/fcvm.2024.1417701.

The Marine Natural Compound Dragmacidin D Selectively Induces Apoptosis in Triple-Negative Breast Cancer Spheroids.

Guzman E, Peterson T, Wright A Mar Drugs. 2023; 21(12).

PMID: 38132962 PMC: 10871089. DOI: 10.3390/md21120642.

Proscillaridin A inhibits lung cancer cell growth and motility through downregulation of the EGFR-Src-associated pathway.

Tsai J, Weng C, Lai Y, Tsai M, Chen H, Chen J Am J Cancer Res. 2023; 13(11):5352-5367.

PMID: 38058797 PMC: 10695799.

References

Kimura A, Horikoshi M . Tip60 acetylates six lysines of a specific class in core histones in vitro. Genes Cells. 1999; 3(12):789-800. DOI: 10.1046/j.1365-2443.1998.00229.x. View

Felsher D, Bishop J . Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell. 1999; 4(2):199-207. DOI: 10.1016/s1097-2765(00)80367-6. View

Bellavia D, Campese A, Vacca A, Gulino A, Screpanti I . Notch3, another Notch in T cell development. Semin Immunol. 2003; 15(2):107-12. DOI: 10.1016/s1044-5323(03)00007-1. View

Frank S, Parisi T, Taubert S, Fernandez P, Fuchs M, Chan H . MYC recruits the TIP60 histone acetyltransferase complex to chromatin. EMBO Rep. 2003; 4(6):575-80. PMC: 1319201. DOI: 10.1038/sj.embor.embor861. View

Vervoorts J, Luscher-Firzlaff J, Rottmann S, Lilischkis R, Walsemann G, Dohmann K . Stimulation of c-MYC transcriptional activity and acetylation by recruitment of the cofactor CBP. EMBO Rep. 2003; 4(5):484-90. PMC: 1319176. DOI: 10.1038/sj.embor.embor821. View

Marinkovic D, Marinkovic T, Mahr B, Hess J, Wirth T . Reversible lymphomagenesis in conditionally c-MYC expressing mice. Int J Cancer. 2004; 110(3):336-42. DOI: 10.1002/ijc.20099. View

Patel J, Du Y, Ard P, Phillips C, Carella B, Chen C . The c-MYC oncoprotein is a substrate of the acetyltransferases hGCN5/PCAF and TIP60. Mol Cell Biol. 2004; 24(24):10826-34. PMC: 533976. DOI: 10.1128/MCB.24.24.10826-10834.2004. View

Kometiani P, Liu L, Askari A . Digitalis-induced signaling by Na+/K+-ATPase in human breast cancer cells. Mol Pharmacol. 2004; 67(3):929-36. DOI: 10.1124/mol.104.007302. View

Zhang K, Faiola F, Martinez E . Six lysine residues on c-Myc are direct substrates for acetylation by p300. Biochem Biophys Res Commun. 2005; 336(1):274-80. DOI: 10.1016/j.bbrc.2005.08.075. View

10.

Faiola F, Liu X, Lo S, Pan S, Zhang K, Lymar E . Dual regulation of c-Myc by p300 via acetylation-dependent control of Myc protein turnover and coactivation of Myc-induced transcription. Mol Cell Biol. 2005; 25(23):10220-34. PMC: 1291249. DOI: 10.1128/MCB.25.23.10220-10234.2005. View

11.

Kuhns M, Davis M, Garcia K . Deconstructing the form and function of the TCR/CD3 complex. Immunity. 2006; 24(2):133-9. DOI: 10.1016/j.immuni.2006.01.006. View

12.

Avvakumov N, Cote J . The MYST family of histone acetyltransferases and their intimate links to cancer. Oncogene. 2007; 26(37):5395-407. DOI: 10.1038/sj.onc.1210608. View

13.

Prassas I, Diamandis E . Novel therapeutic applications of cardiac glycosides. Nat Rev Drug Discov. 2008; 7(11):926-35. DOI: 10.1038/nrd2682. View

14.

Cox J, Mann M . MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008; 26(12):1367-72. DOI: 10.1038/nbt.1511. View

15.

Tremblay M, Tremblay C, Herblot S, Aplan P, Hebert J, Perreault C . Modeling T-cell acute lymphoblastic leukemia induced by the SCL and LMO1 oncogenes. Genes Dev. 2010; 24(11):1093-105. PMC: 2878648. DOI: 10.1101/gad.1897910. View

16.

Jain S, Vaidyanathan B . Digoxin in management of heart failure in children: Should it be continued or relegated to the history books?. Ann Pediatr Cardiol. 2010; 2(2):149-52. PMC: 2922663. DOI: 10.4103/0974-2069.58317. View

17.

Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith W, Fedorov O . Selective inhibition of BET bromodomains. Nature. 2010; 468(7327):1067-73. PMC: 3010259. DOI: 10.1038/nature09504. View

18.

Luebben W, Sharma N, Nyborg J . Nucleosome eviction and activated transcription require p300 acetylation of histone H3 lysine 14. Proc Natl Acad Sci U S A. 2010; 107(45):19254-9. PMC: 2984149. DOI: 10.1073/pnas.1009650107. View

19.

Jin Q, Yu L, Wang L, Zhang Z, Kasper L, Lee J . Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation. EMBO J. 2010; 30(2):249-62. PMC: 3025463. DOI: 10.1038/emboj.2010.318. View

20.

Delgado M, Leon J . Myc roles in hematopoiesis and leukemia. Genes Cancer. 2011; 1(6):605-16. PMC: 3092227. DOI: 10.1177/1947601910377495. View