Dual functions of the homeoprotein DLX4 in modulating responsiveness of tumor cells to topoisomerase II-targeting drugs.

Cancer Res 2013 Jan 15; 73(2):1000-10.

Trinh BQ, Ko SY, Barengo N, Lin SY, Naora H.

 

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 (DSBs). Several lines of evidence indicate that overexpression of TOP2A, the gene encoding topoisomerase IIa, 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.

 

SUPPLEMENTARY

The study by Trinh et al. focused on investigating the determinants of sensitivity of tumors to drugs that target the enzyme topoisomerase II (TOP2). TOP2 has two isoforms (TOP2a, TOP2b) and induces transient DNA double-strand breaks (DSBs) to relieve torsional stress imposed on DNA during replication. Anthracyclines and etoposide are TOP2 poisons that cause DSBs to accumulate to lethal levels by trapping TOP2 in a complex with DNA. Previous experimental studies by other groups have demonstrated that overexpression of TOP2A, the gene encoding TOP2a, increases TOP2 poison-induced cell death. However, there have been conflicting studies regarding the clinical value of TOP2A for predicting responsiveness to TOP2 poisons.

Trinh et al. identified two opposing activities of a transcription factor that could explain why some TOP2A-overexpressing tumors respond poorly to TOP2 poisons. Firstly, the authors identified that expression of the TOP2A gene is induced by DLX4, a transcription factor that is frequently overexpressed in breast and ovarian cancers. Secondly, it was found that DLX4 decreases TOP2 poison-induced cell death by stimulating repair of DSBs. Repair of DSBs by the canonical non-homologous end-joining (NHEJ) pathway is initiated by the binding of Ku70-Ku80 heterodimers to DNA ends which then recruit the catalytic subunit of DNA-dependent protein kinase (DNA-PK) to form a complex that enables ligation of DNA ends. DLX4 was found to interact with Ku70 and Ku80, stimulate DNA-PK activity and increase end-joining repair of DSBs. In contrast to homologous recombination-mediated DNA repair, DNA repair by NHEJ is error-prone. Interestingly, Trinh et al. identified that DLX4 not only stimulated the frequency of end-joining repair, but also increased the magnitude of erroneous repair.

Collectively, the findings that DLX4 induces TOP2A expression and also stimulates repair of DSBs provide a molecular explanation as why some tumors that overexpress TOP2A are not highly sensitive to TOP2 poisons. DLX4 might therefore be a useful marker, when combined with TOP2a, for predicting responsiveness to TOP2 poisons. In addition, the finding that DLX4 stimulates erroneous repair of DSBs raises the possibility that overexpression of DLX4 in tumors could contribute to genomic instability.

Honami Naora-2

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