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; Jian Shi

doi:10.1038/s41467-018-07258-y

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

Nat Commun. 2018 Dec 5;9(1):5200. doi: 10.1038/s41467-018-07258-y.

Authors

Jingyi Liu^{1

2

3}, Zhibing Duan^{1

2}, Weijie Guo^{1

2}, Lei Zeng^{4

5}, Yadi Wu^{2

6}, Yule Chen^{1

2}, Fang Tai^{7

8

9}, Yifan Wang^{1

2}, Yiwei Lin^{1

2}, Qiang Zhang^{4

5}, Yanling He^{7

8

9}, Jiong Deng¹⁰, Rachel L Stewart², Chi Wang², Pengnian Charles Lin³, Saghi Ghaffari¹¹, B Mark Evers^{2

12}, Suling Liu¹³, Ming-Ming Zhou¹⁴, Binhua P Zhou^{15

16}, Jian Shi^{17

18

19

20

21}

Affiliations

¹ Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
² Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
³ Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, 21702, USA.
⁴ Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
⁵ Bethune Institute of Epigenetic Medicine, The First Hospital, Jilin University, Changchun, Jilin, 130021, China.
⁶ Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
⁷ Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.
⁸ Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
⁹ Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, Guangdong, 510515, China.
¹⁰ Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
¹¹ Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
¹² Department of Surgery, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
¹³ Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. suling@fudan.edu.cn.
¹⁴ Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. ming-ming.zhou@mssm.edu.
¹⁵ Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, 40506, USA. peter.zhou@uky.edu.
¹⁶ Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40506, USA. peter.zhou@uky.edu.
¹⁷ Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, 40506, USA. jianshi@smu.edu.cn.
¹⁸ Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40506, USA. jianshi@smu.edu.cn.
¹⁹ Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China. jianshi@smu.edu.cn.
²⁰ Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China. jianshi@smu.edu.cn.
²¹ Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, Guangdong, 510515, China. jianshi@smu.edu.cn.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Acetylation / drug effects
Animals
Breast Neoplasms / drug therapy
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Cell Cycle Proteins
Cell Line, Tumor
Cell Nucleus / genetics
Cell Nucleus / metabolism
Cyclin-Dependent Kinase 6 / genetics
Cyclin-Dependent Kinase 6 / metabolism*
Female
Forkhead Box Protein O3 / genetics
Forkhead Box Protein O3 / metabolism*
Gene Expression Regulation
Heterocyclic Compounds, 3-Ring / administration & dosage
Humans
Mice
Mice, Nude
Nuclear Proteins / chemistry
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Oxadiazoles / administration & dosage
Promoter Regions, Genetic
Protein Binding / drug effects
Protein Domains
Protein Kinase Inhibitors / administration & dosage
Protein Transport / drug effects
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism*
Pyrimidines / administration & dosage
Pyrroles / administration & dosage
Sirtuins / genetics
Sirtuins / metabolism
Transcription Factors / chemistry
Transcription Factors / genetics
Transcription Factors / metabolism*

Substances

BRD4 protein, human
Cell Cycle Proteins
FOXO3 protein, human
Forkhead Box Protein O3
GSK690693
Heterocyclic Compounds, 3-Ring
MK 2206
Nuclear Proteins
Oxadiazoles
Protein Kinase Inhibitors
Pyrimidines
Pyrroles
Transcription Factors
Proto-Oncogene Proteins c-akt
CDK6 protein, human
Cyclin-Dependent Kinase 6
SIRT6 protein, human
Sirtuins
capivasertib

Abstract

Publication types

MeSH terms

Substances

Grants and funding