The emerging role of H3K9me3 as a potential therapeutic target in acute myeloid leukaemia

Monaghan, L., Massett, M. E., Bunschoten, R. P., Hoose, A., Pirvan, P.-A., Liskamp, R. M.J. , Jørgensen, H. G. and Huang, X. (2019) The emerging role of H3K9me3 as a potential therapeutic target in acute myeloid leukaemia. Frontiers in Oncology, 9, 705. (doi: 10.3389/fonc.2019.00705) (PMID:31428579) (PMCID:PMC6687838)

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Growing evidence has demonstrated that epigenetic dysregulation is a common pathological feature in human cancer cells. Global alterations in the epigenetic landscape are prevalent in malignant cells across different solid tumours including, prostate cancer, non-small-cell lung cancer, renal cell carcinoma, and in haemopoietic malignancy. In particular, DNA hypomethylation and histone hypoacetylation have been observed in acute myeloid leukaemia (AML) patient blasts, with histone methylation being an emerging area of study. Histone 3 lysine 9 trimethylation (H3K9me3) is a post-translational modification known to be involved in the regulation of a broad range of biological processes, including the formation of transcriptionally silent heterochromatin. Following the observation of its aberrant methylation status in haematological malignancy and several other cancer phenotypes, recent studies have associated H3K9me3 levels with patient outcome and highlighted key molecular mechanisms linking H3K9me3 profile with AML aetiology in a number of large-scale meta-analysis. Consequently, the development and application of small molecule inhibitors which target the histone methyltransferases or demethylase enzymes known to participate in the oncogenic regulation of H3K9me3 in AML represents an advancing area of ongoing study. Here, we provide a comprehensive review on how this particular epigenetic mark is regulated within cells and its emerging role as a potential therapeutic target in AML, along with an update on the current research into advancing the generation of more potent and selective inhibitors against known H3K9 methyltransferases and demethylases.

Item Type:Articles
Additional Information:This work was supported by the Howat Foundation and Friends of Paul O’Gorman; and SULSAPECRE; X.H. is a John Goldman Fellow; LM is a recipient of Adam Renwick Martin-Friends of Paul O’Gorman PhD Studentship.
Glasgow Author(s) Enlighten ID:Liskamp, Professor Robert and Bunschoten, Mr Roderick and Massett, Mr Matthew and Hoose, Mr Alex and Huang, Dr Xu and Monaghan, Miss Laura and Pirvan, Mr Petrisor-Alin and Jorgensen, Dr Heather
Authors: Monaghan, L., Massett, M. E., Bunschoten, R. P., Hoose, A., Pirvan, P.-A., Liskamp, R. M.J., Jørgensen, H. G., and Huang, X.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Science and Engineering > School of Chemistry
Journal Name:Frontiers in Oncology
Publisher:Frontiers Media
ISSN (Online):2234-943X
Copyright Holders:Copyright © 2019 Monaghan, Massett, Bunschoten, Hoose, Pirvan, Liskamp, Jørgensen and Huang
First Published:First published in Frontiers in Oncology 9:705
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
712951Delineation of the critical epigenetic regulatory machinery selective for acute myeloid leukaemia stem cell functionXu HuangLeuka (LEUKA)2016/JGF/0005ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C
632234Funding SchemesAnna DominiczakWellcome Trust (WELLCOTR)105614/Z/14/ZRI CARDIOVASCULAR & MEDICAL SCIENCES