Oncotarget

Research Papers:

The histone deacetylase inhibitor Romidepsin induces as a cascade of differential gene expression and altered histone H3K9 marks in myeloid leukaemia cells

Kathryn Clarke, Christine Young, Fabio Liberante, Mary-Frances McMullin, Alexander Thompson and Ken Mills _

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Oncotarget. 2019; 10:3462-3471. https://doi.org/10.18632/oncotarget.26877

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Abstract

Kathryn Clarke1,2, Christine Young1,3, Fabio Liberante1,4, Mary-Frances McMullin1,5, Alexander Thompson1,6 and Ken Mills1

1 Blood Cancer Research Group, Centre for Cancer Research and Cell Biology (CCRCB), Queen’s University Belfast, Belfast, United Kingdom

2 Current address: Department of Haematology, Addenbrooke’s Hospital, Cambridge, United Kingdom

3 Current address: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom

4 Current address: Ludwig Boltzmann Institute for Cancer Research, Wien, Austria

5 Centre for Medical Education, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Belfast, United Kingdom

6 Current address: Division of Cancer and Stem Cells, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, United Kingdom

Correspondence to:

Ken Mills,email: k.mills@qub.ac.uk

Keywords: HDAC inhibitor; epigenetic; transcriptional regulation; myelodysplastic syndrome (MDS)

Received: August 09, 2018     Accepted: April 03, 2019     Published: May 28, 2019

ABSTRACT

Myelodysplastic syndromes (MDS) are a heterogeneous, clonal haematopoietic disorder, with ~1/3 of patients progressing to acute myeloid leukaemia (AML). Many elderly MDS patients do not tolerate intensive therapeutic regimens, and therefore have an unmet need for better tolerated therapies.

Epigenetics is important in the pathogenesis of MDS/AML with DNA methylation, and histone acetylation the most widely studied modifications. Epigenetic therapeutic agents have targeted the reversible nature of these modifications with some clinical success. The aim of this study was to characterise the molecular consequences of treatment of MDS and AML cells with the histone deacetylase inhibitor (HDACi) Romidepsin.

Romidepsin as a single agent induced cell death with an increasing dose and time profile associated with increased acetylation of histone H3 lysine 9 (H3K9) and decreased HDAC activity. Gene expression profiling, qPCR, network and pathway analysis recognised that oxidation-reduction was involved in response to Romidepsin. ROS was implicated as being involved post-treatment with the involvement of TSPO and MPO.

Genomic analysis uncoupled the differences in protein-DNA interactions and gene regulation. The spatial and temporal transcriptional differences associated with acetylated, mono- and tri-methylated H3K9, representative of two activation and a repression mark respectively, were identified. Bioinformatic analysis uncovered positional enrichment and transcriptional differences between these marks; a degree of overlap with increased/decreased gene expression that correlates to increased/decreased histone modification. Overall, this study has unveiled a number of underlying mechanisms of the HDACi Romidepsin that could identify potential drug combinations for use in the clinic.


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