Ym155 Suppresses Survivin Expression By Disrupting The Ilf3/P54(Nrb) Transcription Factor Complex

Survivin, a member of the anti-apoptosis proteins family, is highly expressed in all primary tumor types, and is responsible for cancer progression and drug resistance in many types of cancer. YM155, a small chemical compound, selectively suppressed the expression of survivin and induced apoptosis in cancer cells both in vitro and in vivo. However, the mechanisms underlying the suppression of survivin expression by YM155 are unknown. In order to identify the molecular targets and analyze the drug mechanism of action, affinity purification was performed using an active analogue of YM155. We identified interleukin enhancer-binding factor 3 (ILF3) as the binding target of YM155. From the complex analysis of ILF3 and survivin promoter sequence, we also found that ILF3 forms a complex with p54nrb transcription factor, and then binds to the survivin promoter. Overexpression of ILF3 enhanced survivin promoter activity, which was attenuated by YM155 in a concentration-dependent manner. Furthermore, the ILF3/p54nrb complex was disrupted by YM155, thus dispersing the components in the nucleus.In conclusion, our study suggests that binding to ILF3 by YM155 causes the dissociation of the ILF3/p54nrb complex, thus inhibits ILF3 dependent survivin expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4756. doi:1538-7445.AM2012-4756