PMID- 33811160
OWN - NLM
STAT- MEDLINE
DCOM- 20220210
LR  - 20221005
IS  - 1557-3125 (Electronic)
IS  - 1541-7786 (Print)
IS  - 1541-7786 (Linking)
VI  - 19
IP  - 8
DP  - 2021 Aug
TI  - Autophagy-Dependent Sensitization of Triple-Negative Breast Cancer Models to 
      Topoisomerase II Poisons by Inhibition of the Nucleosome Remodeling Factor.
PG  - 1338-1349
LID - 10.1158/1541-7786.MCR-20-0743 [doi]
AB  - 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.
CI  - (c)2021 American Association for Cancer Research.
FAU - Tyutyunyk-Massey, Liliya
AU  - Tyutyunyk-Massey L
AD  - VCU Massey Cancer Center, Department of Pharmacology and Toxicology, Virginia 
      Commonwealth University School of Medicine, Richmond, Virginia.
FAU - Sun, Yilun
AU  - Sun Y
AUID- ORCID: 0000-0002-6249-2704
AD  - Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, 
      Center for Cancer Research, NIH, Bethesda, Maryland.
FAU - Dao, Nga
AU  - Dao N
AUID- ORCID: 0000-0002-5065-6564
AD  - VCU Massey Cancer Center, Department of Human and Molecular Genetics, Virginia 
      Commonwealth University School of Medicine, Richmond, Virginia.
FAU - Ngo, Hannah
AU  - Ngo H
AD  - VCU Massey Cancer Center, Department of Human and Molecular Genetics, Virginia 
      Commonwealth University School of Medicine, Richmond, Virginia.
FAU - Dammalapati, Mallika
AU  - Dammalapati M
AD  - VCU Massey Cancer Center, Department of Human and Molecular Genetics, Virginia 
      Commonwealth University School of Medicine, Richmond, Virginia.
FAU - Vaidyanathan, Ashish
AU  - Vaidyanathan A
AUID- ORCID: 0000-0001-7927-188X
AD  - VCU Massey Cancer Center, Department of Human and Molecular Genetics, Virginia 
      Commonwealth University School of Medicine, Richmond, Virginia.
FAU - Singh, Manjulata
AU  - Singh M
AUID- ORCID: 0000-0003-0297-0636
AD  - VCU Massey Cancer Center, Department of Human and Molecular Genetics, Virginia 
      Commonwealth University School of Medicine, Richmond, Virginia.
FAU - Haqqani, Syed
AU  - Haqqani S
AD  - VCU Massey Cancer Center, Department of Human and Molecular Genetics, Virginia 
      Commonwealth University School of Medicine, Richmond, Virginia.
FAU - Haueis, Joshua
AU  - Haueis J
AD  - VCU Massey Cancer Center, Department of Human and Molecular Genetics, Virginia 
      Commonwealth University School of Medicine, Richmond, Virginia.
FAU - Finnegan, Ryan
AU  - Finnegan R
AD  - VCU Massey Cancer Center, Department of Pharmacology and Toxicology, Virginia 
      Commonwealth University School of Medicine, Richmond, Virginia.
FAU - Deng, Xiaoyan
AU  - Deng X
AUID- ORCID: 0000-0003-0207-0769
AD  - VCU Massey Cancer Center, Department of Biostatistics, Virginia Commonwealth 
      University School of Medicine, Richmond, Virginia.
FAU - Kirberger, Steve E
AU  - Kirberger SE
AD  - Department of Chemistry, University of Minnesota, Minneapolis, Minnesota.
FAU - Bos, Paula D
AU  - Bos PD
AUID- ORCID: 0000-0001-8035-5888
AD  - VCU Massey Cancer Center, Department of Pathology, Virginia Commonwealth 
      University School of Medicine, Richmond, Virginia.
FAU - Bandyopadhyay, Dipankar
AU  - Bandyopadhyay D
AD  - VCU Massey Cancer Center, Department of Biostatistics, Virginia Commonwealth 
      University School of Medicine, Richmond, Virginia.
FAU - Pomerantz, William C K
AU  - Pomerantz WCK
AD  - Department of Chemistry, University of Minnesota, Minneapolis, Minnesota.
FAU - Pommier, Yves
AU  - Pommier Y
AD  - Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, 
      Center for Cancer Research, NIH, Bethesda, Maryland.
FAU - Gewirtz, David A
AU  - Gewirtz DA
AD  - VCU Massey Cancer Center, Department of Pharmacology and Toxicology, Virginia 
      Commonwealth University School of Medicine, Richmond, Virginia.
FAU - Landry, Joseph W
AU  - Landry JW
AD  - VCU Massey Cancer Center, Department of Human and Molecular Genetics, Virginia 
      Commonwealth University School of Medicine, Richmond, Virginia. 
      joseph.landry@vcuhealth.org.
LA  - eng
GR  - P30 CA016059/CA/NCI NIH HHS/United States
GR  - R01 GM121414/GM/NIGMS NIH HHS/United States
GR  - R35 GM140837/GM/NIGMS NIH HHS/United States
GR  - Z01 BC006161/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20210402
PL  - United States
TA  - Mol Cancer Res
JT  - Molecular cancer research : MCR
JID - 101150042
RN  - 0 (Antigens, Nuclear)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nucleosomes)
RN  - 0 (Transcription Factors)
RN  - 0 (fetal Alzheimer antigen)
RN  - 80168379AG (Doxorubicin)
RN  - EC 5.99.1.3 (DNA Topoisomerases, Type II)
SB  - IM
MH  - Animals
MH  - Antigens, Nuclear/genetics
MH  - Antineoplastic Agents/pharmacology
MH  - Apoptosis/drug effects/genetics
MH  - Autophagy/drug effects/*genetics
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - DNA Topoisomerases, Type II/*genetics
MH  - Doxorubicin/pharmacology
MH  - Female
MH  - HEK293 Cells
MH  - Humans
MH  - MCF-7 Cells
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Nerve Tissue Proteins/genetics
MH  - Nucleosomes/*genetics
MH  - Transcription Factors/genetics
MH  - Triple Negative Breast Neoplasms/drug therapy/*genetics
PMC - PMC8667864
MID - NIHMS1691230
COIS- Conflict of Interest: The authors declare no conflicts of interest.
EDAT- 2021/04/04 06:00
MHDA- 2022/02/11 06:00
PMCR- 2022/02/01
CRDT- 2021/04/03 05:36
PHST- 2020/08/29 00:00 [received]
PHST- 2021/02/23 00:00 [revised]
PHST- 2021/03/29 00:00 [accepted]
PHST- 2021/04/04 06:00 [pubmed]
PHST- 2022/02/11 06:00 [medline]
PHST- 2021/04/03 05:36 [entrez]
PHST- 2022/02/01 00:00 [pmc-release]
AID - 1541-7786.MCR-20-0743 [pii]
AID - 10.1158/1541-7786.MCR-20-0743 [doi]
PST - ppublish
SO  - Mol Cancer Res. 2021 Aug;19(8):1338-1349. doi: 10.1158/1541-7786.MCR-20-0743. 
      Epub 2021 Apr 2.