title: Dual functions of the homeoprotein DLX4 in modulating responsiveness of tumor cells to topoisomerase II-targeting drugs.
abstract: Topoisomerase II (TOP2)-targeting poisons such as anthracyclines and etoposide are commonly used for cancer chemotherapy and kill tumor cells by causing accumulation of DNA double-strand breaks (DSB). Several lines of evidence indicate that overexpression of TOP2A, the gene encoding topoisomerase IIα, increases sensitivity of tumor cells to TOP2 poisons, but it is not clear why some TOP2A-overexpressing (TOP2A-High) tumors respond poorly to these drugs. In this study, we identified that TOP2A expression is induced by DLX4, a homeoprotein that is overexpressed in breast and ovarian cancers. Analysis of breast cancer datasets revealed that TOP2A-high cases that also highly expressed DLX4 responded more poorly to anthracycline-based chemotherapy than TOP2A-high cases that expressed DLX4 at low levels. Overexpression of TOP2A alone in tumor cells increased the level of DSBs induced by TOP2 poisons. In contrast, DLX4 reduced the level of TOP2 poison-induced DSBs irrespective of its induction of TOP2A. DLX4 did not stimulate homologous recombination-mediated repair of DSBs. However, DLX4 interacted with Ku proteins, stimulated DNA-dependent protein kinase activity, and increased erroneous end-joining repair of DSBs. Whereas DLX4 did not reduce levels of TOP2 poison-induced DSBs in Ku-deficient cells, DLX4 stimulated DSB repair and reduced the level of TOP2 poison-induced DSBs when Ku was reconstituted in these cells. Our findings indicate that DLX4 induces TOP2A expression but reduces sensitivity of tumor cells to TOP2 poisons by stimulating Ku-dependent repair of DSBs. These opposing activities of DLX4 could explain why some TOP2A-overexpressing tumors are not highly sensitive to TOP2 poisons.
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
authors.forename: Bon Q
authors.initials: BQ
authors.lastname: Trinh
authors.forename: Song Yi
authors.initials: SY
authors.lastname: Ko
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barengo
authors.forename: Shiaw-Yih
authors.initials: SY
authors.lastname: Lin
authors.forename: Honami
authors.initials: H
authors.lastname: Naora
mesh_terms: D018943:Anthracyclines / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000378:metabolism; D004260:DNA Repair; D004250:DNA Topoisomerases, Type II / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D000072200:Ku Autoantigen; D000075223:Poly-ADP-Ribose Binding Proteins; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018943:Anthracyclines; D000951:Antigens, Neoplasm; C105304:DLX4 protein, human; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D014157:Transcription Factors; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human