Abstract 3112: The homeoprotein DLX4 induces topoisomerase IIα expression but reduces sensitivity of tumor cells to topoisomerase II poisons.

Abstract

Abstract Chemotherapeutic drugs such as anthracyclines and etoposide that target topoisomerase II (TOP2) induce tumor cell death by causing accumulation of DNA double-strand breaks (DSBs). Experimental studies have shown that overexpression of topoisomerase IIα (TOP2A) increases sensitivity to TOP2 poisons. However, the clinical value of TOP2A in predicting responsiveness to TOP2 poisons has been controversial and it is not known why some TOP2A-overexpressing tumors respond poorly to these drugs. We identified that expression of TOP2A, the gene encoding TOP2, 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 expressed DLX4 at low levels responded more favorably to anthracycline-based chemotherapy than TOP2A-High cases that also highly expressed DLX4. Overexpression of TOP2A alone in tumor cells increased sensitivity to TOP2 poisons. However, DLX4 decreased sensitivity to these drugs irrespective of its induction of TOP2A. We identified that DLX4 stimulates repair of DSBs and interacts with Ku proteins that are components of the non-homologous end-joining machinery. DLX4 did not reduce levels of TOP2 poison-induced DSBs in Ku-deficient cells, but reduced the level of DSBs when Ku was reconstituted in these cells. Taken together, our findings indicate that DLX4 induces TOP2A expression, but reduces the sensitivity of tumor cells to TOP2 poisons by stimulating Ku-dependent repair of DSBs. These dual and opposing effects of DLX4 could explain why some tumors with elevated TOP2A levels are not highly sensitive to TOP2 poisons. Citation Format: Bon Q. Trinh, Song Yi Ko, Nicolas Barengo, Shiaw-Yih Lin, Honami Naora. The homeoprotein DLX4 induces topoisomerase IIα expression but reduces sensitivity of tumor cells to topoisomerase II poisons. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3112. doi:10.1158/1538-7445.AM2013-3112