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. Implications: These studies suggest NURF can be inhibited pharmacologically as a viable strategy to improve chemotherapy effectiveness.

中文翻译：

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通过抑制核小体重塑因子对三阴性乳腺癌模型对拓扑异构酶 II 毒物的自噬依赖性敏感性

表观遗传调节剂可以调节癌症治疗的效果。为了进一步观察这些观察，我们发现核小体重塑因子 (NURF) 的溴结构域 PHD 指转录因子亚基 (BPTF) 促进了 4T1 乳腺肿瘤细胞系对阿霉素、依托泊苷和紫杉醇的抗性。BPTF 的作用是促进对阿霉素和依托泊苷的抗性，但对紫杉醇没有作用，并且可能对癌细胞具有选择性，因为在胚胎干细胞中没有观察到类似的作用。BPTF 敲低 (KD) 对阿霉素和依托泊苷的敏感性与 DNA 损伤、拓扑异构酶 II (TOP2) 交联和自噬增加有关；然而，只有适度的细胞凋亡增加，而衰老没有增加。使用 BPTF 的遗传和药理学抑制作用，在同基因 4T1 乳腺肿瘤模型中体内证实了对多柔比星的敏感性。基于遗传自噬抑制，体内 BPTF 抑制的作用是自噬依赖性的。最后，用选择性 BPTF 溴结构域抑制剂 AU1 治疗 4T1、66cl4、4T07、MDA-MB-231，而不是 ER 阳性 67NR 和 MCF7 乳腺癌细胞，概括了遗传 BPTF 抑制，包括对阿霉素的体外敏感性，增加了 TOP2 -DNA交联和DNA损伤。总之，这些研究表明，BPTF 对 TOP2 毒物的抗肿瘤活性具有抗性，阻止了 TOP2 交联和相关自噬的解决。这些研究表明，BPTF 可以用小分子抑制剂靶向，以增强 TOP2 靶向癌症化疗药物的有效性。启示：这些研究表明 NURF 可以作为提高化疗效果的可行策略在药理学上受到抑制。