DNA Topoisomerase II Poison TAS-103 Transactivates GC-Box-dependent Transcription via Acetylation of Sp1

Kazuo Chijiiwa,Ken-ichi Matsuo,Tomonori Igarashi,Ichiro Niina,Takayuki Torigoe,Takeshi Yoshida,Izumi Shibuya,Tetsuro Wakasugi,Hiroto Izumi,Hideaki Itoh,Kimitoshi Kohno

doi:10.1074/jbc.m410499200

Abstract

Drug-induced modifications of transcription factors play important roles in both apoptosis and survival signaling. The data presented here show that the DNA topoisomerase II poison TAS-103 transactivated the SV40 promoter in a GC-box-dependent manner and induced Sp1 acetylation in cells expressing p300. This activity was not observed in cells lacking p300. TAS-103 treatment also enhanced the p300 content of the nucleus and the interaction of p300 with Sp1. Cellular susceptibility to TAS-103 was correlated with p300 expression but not with topoisomerase II expression. Furthermore, the presence of p300 significantly sensitized cancer cells to TAS-103 but not to cisplatin. Taken together, these findings demonstrate novel genomic responses to anticancer agents that modulate Sp1 acetylation and Sp1-dependent transcription in an apoptotic pathway.

Highlights

Drug-induced modifications of transcription factors play important roles in both apoptosis and survival signaling
We propose that p300-dependent acetylation of Sp1 triggered through the DNA-damage signaling pathway and cellular acidosis leads to the enhanced expression of Sp1 target genes in TAS-103-induced apoptosis
We have previously identified several transcription factors involved in genomic responses to anticancer agents including Y-box-binding protein-1 (YB-1), activating transcription factor 4 (ATF4), zinc-finger factor 143 (ZNF143), and mitochondrial transcription factor A [21,22,23,24]