Histone deacetylase inhibition redistributes topoisomerase II beta from heterochromatin to euchromatin

The genome is organized into large scale structures in the interphase nucleus. Pericentromeric heterochromatin represents one such compartment characterized by histones H3 and H4 tri-methylated at K9 and K20 respectively and with a correspondingly low level of histone acetylation. HP1 proteins are concentrated in pericentric heterochromatin and histone deacetylase inhibitors such as trichostatin A (TSA) promote hyperacetylation of heterochromatic nucleosomes and the dispersal of HP1 proteins. We observed that in mouse cells, which contain prominent heterochromatin, DNA topoisomerase II beta (topoII beta) is also concentrated in heterochromatic regions. Similarly, a detergent-resistant fraction of topoII beta is associated with heterochromatin in human cell lines. Treatment with TSA displaced topoII beta from the heterochromatin with similar kinetics to the displacement of HP1 beta. Topoisomerase II is the cellular target for a number of clinically important cytotoxic anti-cancer agents known collectively as topoisomerase poisons, and it has been previously reported that histone deacetylase inhibitors can sensitize cells to these drugs. While topoII alpha appears to be the major target for most topoisomerase poisons, histone deacetylase-mediated potentiation of these drugs is dependent on topoII beta. We find that while prior treatment with TSA did not increase the quantity of etoposide-mediated topoII beta-DNA covalent complexes, it did result in a shift in their distribution from a largely heterochromatin-associated to a pan-nuclear pattern. We suggest that this redistribution of topoII beta converts this isoform of topoII to a effective relevant target for topoisomerase poisons.