Autophagy-Dependent Sensitization of Triple-Negative Breast Cancer Models to Topoisomerase II Poisons by Inhibition of the Nucleosome Remodeling Factor
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 02, 2021
- Source ID
- 10.1158/1541-7786.mcr-20-0743
Entities
People
- Ashish Vaidyanathan
- David A. Gewirtz
- Dipankar Bandyopadhyay
- Hannah Ngo
- Joseph W Landry
- Joshua Haueis
- Liliya Tyutyunyk-massey
- Mallika Dammalapati
- Manjulata Singh
- Nga Dao
- Paula D Bos
- Ryan Finnegan
- Steve E. Kirberger
- Syed Haqqani
- William C.k. Pomerantz
- Xiaoyan Deng
- Yilun Sun
- Yves Pommier
Organizations
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institutes of Health
- United States Department of Defense
- University of Minnesota
- Virginia Commonwealth University
- Virginia Commonwealth University School of Medicine