DNA topoisomerase inhibitor, etoposide, enhances GC-box-dependent promoter activity via Sp1 phosphorylation.
Modification of transcription factors by anticancer agents plays an important role in both apoptotic and survival signaling. Here we report that both DNA topoisomerase I and II inhibitors such as SN-38 and etoposide, but not cisplatin, 5-fluorouracil or actinomycin D, can induce phosphorylation of the transcription factor Sp1. Furthermore, DNA topoisomerase inhibitors were shown to transactivate GC-box-dependent promoters such as the SV40 and vascular endothelial growth factor promoters. The phosphorylated form of Sp1 was detectable within 30 min of etoposide treatment and was greatly diminished by the presence of the PI3K inhibitor wortmannin and by DNA-dependent protein kinase (DNA-PK) knockdown. We also confirmed that the phosphorylated form of DNA-PK was increased by treatment with both etoposide and SN-38. Taken together, these findings demonstrate a novel genomic response to anticancer agents that induce Sp1 phosphorylation, and might contribute to tumor progression and drug resistance.
Niina
Ichiro
I
Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health, Iseigaoka, Fukuoka, Japan.
Uchiumi
Takeshi
T
Izumi
Hiroto
H
Torigoe
Takayuki
T
Wakasugi
Tetsuro
T
Igarashi
Tomonori
T
Miyamoto
Naoya
N
Onitsuka
Takamitsu
T
Shiota
Masaki
M
Okayasu
Ryuichi
R
Chijiiwa
Kazuo
K
Kohno
Kimitoshi
K
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D004791:Enzyme Inhibitors; D005047:Etoposide / Q000494:pharmacology*; D020862:GC Rich Sequence; D006801:Humans; D000077146:Irinotecan; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D059004:Topoisomerase I Inhibitors; D014162:Transfection; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D016329:Sp1 Transcription Factor; D059004:Topoisomerase I Inhibitors; D005047:Etoposide; D000077146:Irinotecan; D051747:DNA-Activated Protein Kinase; D002166:Camptothecin