title: G9a inhibition potentiates the anti-tumour activity of DNA double-strand break inducing agents by impairing DNA repair independent of p53 status.
abstract: 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.
authors.affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Agarwal
authors.affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK; The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. Electronic address: s.jackson@gurdon.cam.ac.uk.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jackson
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology*; D045325:HCT116 Cells; D006649:Histocompatibility Antigens / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010692:Phleomycins / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D006649:Histocompatibility Antigens; D010692:Phleomycins; D011799:Quinazolines; C495901:TP53 protein, human; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; C561310:UNC 0638; D005047:Etoposide; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase
keywords: Cancer epigenetics; Chemical probes; Chemotherapeutics; Non-homologous end joining; UNC0638