G9a inhibition potentiates the anti-tumour activity of DNA double-strand break inducing agents by impairing DNA repair independent of p53 status
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Agarwal, P., & Jackson, S. (2016). G9a inhibition potentiates the anti-tumour activity of DNA double-strand break inducing agents by impairing DNA repair independent of p53 status. Cancer Letters, 380 467-475. https://doi.org/10.1016/j.canlet.2016.07.009
Cancer cells often exhibit altered epigenetic signatures that can misregulate genes involved in processes such as transcription, proliferation, apoptosis and DNA repair. As regulation of chromatin structure is crucial for DNA repair processes, and both DNA repair and epigenetic controls are deregulated in many cancers, we speculated that simultaneously targeting both might provide new opportunities for cancer therapy. Here, we describe a focused screen that profiled small-molecule inhibitors targeting epigenetic regulators in combination with DNA double-strand break (DSB) inducing agents. We identify UNC0638, a catalytic inhibitor of histone lysine N-methyl-transferase G9a, as hypersensitising tumour cells to low doses of DSB-inducing agents without affecting the growth of the non-tumorigenic cells tested. Similar effects are also observed with another, structurally distinct, G9a inhibitor A-366. We also show that small-molecule inhibition of G9a or siRNA-mediated G9a depletion induces tumour cell death under low DNA damage conditions by impairing DSB repair in a p53 independent manner. Furthermore, we establish that G9a promotes DNA non-homologous end-joining in response to DSB-inducing genotoxic stress. This study thus highlights the potential for using G9a inhibitors as anti-cancer therapeutic agents in combination with DSB-inducing chemotherapeutic drugs such as etoposide.
cancer epigenetics, chemical probes, UNC0638, chemotherapeutics, non-homologous end joining
Research in the S.P.J. laboratory is funded by Cancer Research UK Program Grant C6/A18796 and the European Research Council (DDREAM) grant 268536-DDRREAM. Core infrastructure funding was provided by Cancer Research UK Grant C6946/ A14492 and Wellcome Trust Grant WT092096. S.P.J. receives a salary from the University of Cambridge, supplemented by Cancer Research UK. P.A. was financially supported by CRUK grant C6/ A11224 and ERC grant DDREAM.
Cancer Research UK (A18796)
European Research Council (268536)
Wellcome Trust (092096/Z/10/Z)
Cancer Research UK (A14492)
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External DOI: https://doi.org/10.1016/j.canlet.2016.07.009
This record's URL: https://www.repository.cam.ac.uk/handle/1810/257370
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