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Distinct effects of topoisomerase II inhibitors on tumor cell lines (part 1)

ABSTRACT: One major class of anti-cancer drugs targets topoisomerase II to induce DNA double-strand breaks and cell death of fast growing cells. Here, we compare three members of this class - the antracyclines doxorubicin and aclarubicin, and a chemically unrelated compound, etoposide. Aclarubicin does not induce DNA breaks. We define a new activity for the antracyclines: unsupported histone eviction from ´open´ or loosely packed chromosomal areas reflecting exon and promoter regions. As a result, the epigenome and the transcriptome are strongly affected. Tissue culture cells were treated with doxorubicin, aclarubicin or etoposide for 2 hours. Then drugs were removed by extensive washing. cells were further cultured for indicated days before total RNA were extracted and compared to un-treated control.

ORGANISM(S): Homo sapiens

SUBMITTER: Baoxu Pang 

PROVIDER: E-GEOD-33624 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin.

Pang Baoxu B   Qiao Xiaohang X   Janssen Lennert L   Velds Arno A   Groothuis Tom T   Kerkhoven Ron R   Nieuwland Marja M   Ovaa Huib H   Rottenberg Sven S   van Tellingen Olaf O   Janssen Jeroen J   Huijgens Peter P   Zwart Wilbert W   Neefjes Jacques J  

Nature communications 20130101

DNA topoisomerase II inhibitors are a major class of cancer chemotherapeutics, which are thought to eliminate cancer cells by inducing DNA double-strand breaks. Here we identify a novel activity for the anthracycline class of DNA topoisomerase II inhibitors: histone eviction from open chromosomal areas. We show that anthracyclines promote histone eviction irrespective of their ability to induce DNA double-strand breaks. The histone variant H2AX, which is a key component of the DNA damage respons  ...[more]

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