The heat shock transcription factor, HSF1, stimulates the catalytic engagement of topoisomerase IIβ over topoisomerase IIα

Topoisomerase II (TOP2) poisons, such as etoposide, are potent antineoplastic drugs that also cause significant secondary toxicity to postmitotic cells. Proliferating mammalian cells express two TOP2 isoforms, TOP2A and TOP2B, whereas postmitotic cells only express TOP2B. Selectively targeting TOP2A, but not TOP2B, could thus prevent secondary toxicity in postmitotic cells. Here we report that the heat shock transcription factor, HSF1, facilitates the catalytic engagement of TOP2B on chromatin. Purified HSF1 stimulates the DNA cleavage and relaxation activity of TOP2B. Atomic force microscopy revealed that HSF1 enhances the binding of TOP2B across a range of DNA conformations. Intriguingly, HSF1 preferentially stimulates TOP2B over TOP2A, and knockdown or inhibition of HSF1 reduces the levels of catalytically engaged TOP2B but not TOP2A. Moreover, HSF1 inhibitors suppress the cytotoxicity of TOP2 poisons toward postmitotic cells without compromising their ability to kill cancer cells, revealing a strategy for minimizing the side-effects of TOP2 poison-based chemotherapy.