G9a inhibition potentiates the anti-tumour activity of DNA double-strand break inducing agents by impairing DNA repair independent of p53 status.
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.
['Agarwal|Pallavi|P|', 'Jackson|Stephen P|SP|']
D000903:Antibiotics, Antineoplastic D000971:Antineoplastic Combined Chemotherapy Protocols D017209:Apoptosis D049109:Cell Proliferation D053903:DNA Breaks, Double-Stranded D059766:DNA End-Joining Repair D004305:Dose-Response Relationship, Drug D004791:Enzyme Inhibitors D005047:Etoposide D045325:HCT116 Cells D006649:Histocompatibility Antigens D011495:Histone-Lysine N-Methyltransferase D006801:Humans D009369:Neoplasms D010692:Phleomycins D011799:Quinazolines D034622:RNA Interference D015398:Signal Transduction D013997:Time Factors D059005:Topoisomerase II Inhibitors D014162:Transfection D016159:Tumor Suppressor Protein p53
UNC0638 Chemotherapeutics Cancer epigenetics Chemical probes Non-homologous end joining