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KDM4A regulates HIF-1 levels through H3K9me3

Lookup NU author(s): Dr Tom McAllisterORCiD, Professor Akane Kawamura



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2017 The Author(s). Regions of hypoxia (low oxygen) occur in most solid tumours and cells in these areas are the most aggressive and therapy resistant. In response to decreased oxygen, extensive changes in gene expression mediated by Hypoxia-Inducible Factors (HIFs) contribute significantly to the aggressive hypoxic tumour phenotype. In addition to HIFs, multiple histone demethylases are altered in their expression and activity, providing a secondary mechanism to extend the hypoxic signalling response. In this study, we demonstrate that the levels of HIF-1α are directly controlled by the repressive chromatin mark, H3K9me3. In conditions where the histone demethylase KDM4A is depleted or inactive, H3K9me3 accumulates at the HIF-1α locus, leading to a decrease in HIF-1α mRNA and a reduction in HIF-1α stabilisation. Loss of KDM4A in hypoxic conditions leads to a decreased HIF-1α mediated transcriptional response and correlates with a reduction in the characteristics associated with tumour aggressiveness, including invasion, migration, and oxygen consumption. The contribution of KDM4A to the regulation of HIF-1α is most robust in conditions of mild hypoxia. This suggests that KDM4A can enhance the function of HIF-1α by increasing the total available protein to counteract any residual activity of prolyl hydroxylases.

Publication metadata

Author(s): Dobrynin G, McAllister TE, Leszczynska KB, Ramachandran S, Krieg AJ, Kawamura A, Hammond EM

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2017

Volume: 7

Online publication date: 11/09/2017

Acceptance date: 25/08/2017

Date deposited: 11/10/2019

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group


DOI: 10.1038/s41598-017-11658-3

PubMed id: 28894274


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