Data from Dual Functions of the Homeoprotein DLX4 in Modulating Responsiveness of Tumor Cells to Topoisomerase II-Targeting Drugs

Abstract

<div>Abstract<p>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 <i>TOP2A</i>, the gene encoding topoisomerase IIα, increases sensitivity of tumor cells to TOP2 poisons, but it is not clear why some <i>TOP2A</i>-overexpressing (<i>TOP2A</i>-High) tumors respond poorly to these drugs. In this study, we identified that <i>TOP2A</i> expression is induced by DLX4, a homeoprotein that is overexpressed in breast and ovarian cancers. Analysis of breast cancer datasets revealed that <i>TOP2A</i>-high cases that also highly expressed <i>DLX4</i> responded more poorly to anthracycline-based chemotherapy than <i>TOP2A-</i>high cases that expressed <i>DLX4</i> at low levels. Overexpression of <i>TOP2A</i> 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 <i>TOP2A</i>. 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 <i>TOP2A</i> 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 <i>TOP2A</i>-overexpressing tumors are not highly sensitive to TOP2 poisons. <i>Cancer Res; 73(2); 1000–10. ©2012 AACR</i>.</p></div>