Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer

Jingyi Liu, Zhibing Duan, Weijie Guo, Lei Zeng, Yadi Wu, Yule Chen, Fang Tai, Yifan Wang, Yiwei Lin, Qiang Zhang, Yanling He, Jiong Deng, Rachel L. Stewart, Chi Wang, Pengnian Charles Lin, Saghi Ghaffari, B. Mark Evers, Suling Liu (), Ming-Ming Zhou (), Binhua P. Zhou () and Jian Shi ()
Additional contact information
Jingyi Liu: University of Kentucky College of Medicine
Zhibing Duan: University of Kentucky College of Medicine
Weijie Guo: University of Kentucky College of Medicine
Lei Zeng: Icahn School of Medicine at Mount Sinai
Yadi Wu: University of Kentucky College of Medicine
Yule Chen: University of Kentucky College of Medicine
Fang Tai: Southern Medical University
Yifan Wang: University of Kentucky College of Medicine
Yiwei Lin: University of Kentucky College of Medicine
Qiang Zhang: Icahn School of Medicine at Mount Sinai
Yanling He: Southern Medical University
Jiong Deng: Shanghai Jiao Tong University School of Medicine
Rachel L. Stewart: University of Kentucky College of Medicine
Chi Wang: University of Kentucky College of Medicine
Pengnian Charles Lin: National Cancer Institute-Frederick
Saghi Ghaffari: Icahn School of Medicine at Mount Sinai
B. Mark Evers: University of Kentucky College of Medicine
Suling Liu: Cancer Institute, Fudan University Shanghai Cancer Center
Ming-Ming Zhou: Icahn School of Medicine at Mount Sinai
Binhua P. Zhou: University of Kentucky College of Medicine
Jian Shi: University of Kentucky College of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or CDK6 significantly overcomes the resistance of luminal breast cancer cells to AKT inhibitors in vitro and in vivo. Our study reports the involvement of BRD4/FOXO3a/CDK6 axis in AKTi resistance and provides potential therapeutic strategies for treating resistant breast cancer.

Date: 2018
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-018-07258-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07258-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-07258-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().