G9a inhibition potentiates the anti-tumour activity of DNA double-strand break inducing agents by impairing DNA repair independent of p53 status
Pallavi Agarwal & Stephen P. Jackson. Cancer Lett. 2016 Jul 16; 380(2):467-475.
DOI:10.1016/j.canlet.2016.07.009. [Epub ahead of print]
Highlights from paper
- Cancer cell growth inhibition screen with epigenetic chemical probes and phleomycin.
- G9a inhibitor UNC0638 hypersensitises tumour cells to DNA-damaging agents.
- Under low-level damage, G9a inhibitor induces p53-independent tumour cell death.
- G9a depletion induces tumour cell death by impairing DNA double-strand repair.
- G9a promotes DSB repair by non-homologous end joining.
Abstract from paper
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.
Excerpts reproduced from paper under a Creative Commons licence (CC/BY/4.0).
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