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Supplemental Figure 5 from Autophagy-Dependent Sensitization of Triple-Negative Breast Cancer Models to Topoisomerase II Poisons by Inhibition of the Nucleosome Remodeling Factor

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posted on 2023-04-03, 19:49 authored by Liliya Tyutyunyk-Massey, Yilun Sun, Nga Dao, Hannah Ngo, Mallika Dammalapati, Ashish Vaidyanathan, Manjulata Singh, Syed Haqqani, Joshua Haueis, Ryan Finnegan, Xiaoyan Deng, Steve E. Kirberger, Paula D. Bos, Dipankar Bandyopadhyay, William C.K. Pomerantz, Yves Pommier, David A. Gewirtz, Joseph W. Landry

Supplemental Figure 5. Selective BPTF Bromdomain Inhibitor AU1 Recapitulates Effects from BPTF KD in Human MDA-MB-231 and Mouse 66cl4 and 4T07 Cell Lines.

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Department of Defense

National Institute of General Medical Sciences

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NIH-NCI Cancer Center

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ARTICLE ABSTRACT

Epigenetic regulators can modulate the effects of cancer therapeutics. To further these observations, we discovered that the bromodomain PHD finger transcription factor subunit (BPTF) of the nucleosome remodeling factor (NURF) promotes resistance to doxorubicin, etoposide, and paclitaxel in the 4T1 breast tumor cell line. BPTF functions in promoting resistance to doxorubicin and etoposide, but not paclitaxel, and may be selective to cancer cells, as a similar effect was not observed in embryonic stem cells. Sensitization to doxorubicin and etoposide with BPTF knockdown (KD) was associated with increased DNA damage, topoisomerase II (TOP2) crosslinking and autophagy; however, there was only a modest increase in apoptosis and no increase in senescence. Sensitization to doxorubicin was confirmed in vivo with the syngeneic 4T1 breast tumor model using both genetic and pharmacologic inhibition of BPTF. The effects of BPTF inhibition in vivo are autophagy dependent, based on genetic autophagy inhibition. Finally, treatment of 4T1, 66cl4, 4T07, MDA-MB-231, but not ER-positive 67NR and MCF7 breast cancer cells with the selective BPTF bromodomain inhibitor, AU1, recapitulates genetic BPTF inhibition, including in vitro sensitization to doxorubicin, increased TOP2-DNA crosslinks and DNA damage. Taken together, these studies demonstrate that BPTF provides resistance to the antitumor activity of TOP2 poisons, preventing the resolution of TOP2 crosslinking and associated autophagy. These studies suggest that BPTF can be targeted with small-molecule inhibitors to enhance the effectiveness of TOP2-targeted cancer chemotherapeutic drugs. These studies suggest NURF can be inhibited pharmacologically as a viable strategy to improve chemotherapy effectiveness.

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