Functional interaction of DNA topoisomerase IIα with the β-catenin and T-Cell factor-4 complex

Background & Aims: The Wnt signaling pathway is activated constitutively in the majority of colorectal cancers as a result of mutation in either the adenomatous polyposis coli or the CTNNB1 gene, and blockage of the pathway has been considered feasible as molecular therapy against colorectal cancer. DNA topoisomerase II alpha (Topo II alpha) is a component of the beta-catenin/ T-cell factor-4 (TCF-4) nuclear complex. We examined the functional significance of Topo IIa in Writ signaling. Methods: The physical and functional interaction between Topo II alpha and the beta-catenin/TCF-4 nuclear complex was evaluated by immunoprecipitation, immunofluorescence microscopy, 2-hybrid assay, and luciferase reporter assay. Results: Amino acids 9511301 of Topo II alpha were necessary for binding to beta-catenin. Over expression of Topo II alpha enhanced the TCF/lymphoid enhancer factor transcriptional activity in a dose-dependent manner, and knockdown of Topo II alpha by RNA interference conversely attenuated the transcriptional activity. The Topo II inhibitors, merbarone and etoposide, suppressed the beta-catenin-mediated TCF/lymphoid enhancer factor transcriptional activity. The catalytic activity of Topo II was augmented by overexpression of beta-catenin as measured by the decatenation of kinetoplast DNA. Topo II alpha was highly expressed and colocalized with beta-catenin in tumor cells of patients with familial adenomuatous polyposis syndrome and patients with sporadic colorectal cancer. Conclusions: Topo II alpha interacts with beta-catenin as a novel transcriptional co-activator. A new drug targeting the interaction of Topo II alpha with (beta-catenin as well as its catalytic activity might be more effective for suppressing aberrant Wnt signaling and proliferation of colorectal cancer cells than the current Topo II inhibitors.