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

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. ZhouJian Shi

Research output: Contribution to journal › Article › peer-review

61 Scopus citations

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.

Original language	English
Article number	5200
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07258-y
State	Published - Dec 1 2018

Bibliographical note

Funding Information:
We thank Dr. Claudia Scholl for providing CDK6 expression plasmid. We also thank Dr. Cathy Anthony for critical reading and editing of this manuscript. This research was supported by the Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558) and University of Kentucky Center of Biomedical Research Excellence in Cancer and Metabolism (P20 GM121327). This work was also supported by grants from NIH (CA125454 and CA188118 to B.P.Z., and CA87658 and CA203067 to M.M.Z.), and DoD (BC140733 to M.M.Z. and B.P.Z.). This work was also supported in part by National Natural Science Foundation of China (81672629 to J.S.; 81402434 to Y.W.; 81530075 and 81773155 to S.L.), Science and Technology Program of Guangzhou, China (201707010331 to J.S.), and Basic Public Welfare Research Program of Zhejiang Province (LGF18H290003 to Y.W.).

Publisher Copyright:
© 2018, The Author(s).

ASJC Scopus subject areas

Physics and Astronomy (all)
Chemistry (all)
Biochemistry, Genetics and Molecular Biology (all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-018-07258-y

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Liu, J., Duan, Z., Guo, W., Zeng, L., Wu, Y., Chen, Y., Tai, F., Wang, Y., Lin, Y., Zhang, Q., He, Y., Deng, J., Stewart, R. L., Wang, C., Lin, P. C., Ghaffari, S., Evers, B. M., Liu, S., Zhou, M. M., ... Shi, J. (2018). Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer. Nature Communications, 9(1), Article 5200. https://doi.org/10.1038/s41467-018-07258-y

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title = "Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer",

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.",

author = "Jingyi Liu and Zhibing Duan and Weijie Guo and Lei Zeng and Yadi Wu and Yule Chen and Fang Tai and Yifan Wang and Yiwei Lin and Qiang Zhang and Yanling He and Jiong Deng and Stewart, {Rachel L.} and Chi Wang and Lin, {Pengnian Charles} and Saghi Ghaffari and Evers, {B. Mark} and Suling Liu and Zhou, {Ming Ming} and Zhou, {Binhua P.} and Jian Shi",

note = "Funding Information: We thank Dr. Claudia Scholl for providing CDK6 expression plasmid. We also thank Dr. Cathy Anthony for critical reading and editing of this manuscript. This research was supported by the Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558) and University of Kentucky Center of Biomedical Research Excellence in Cancer and Metabolism (P20 GM121327). This work was also supported by grants from NIH (CA125454 and CA188118 to B.P.Z., and CA87658 and CA203067 to M.M.Z.), and DoD (BC140733 to M.M.Z. and B.P.Z.). This work was also supported in part by National Natural Science Foundation of China (81672629 to J.S.; 81402434 to Y.W.; 81530075 and 81773155 to S.L.), Science and Technology Program of Guangzhou, China (201707010331 to J.S.), and Basic Public Welfare Research Program of Zhejiang Province (LGF18H290003 to Y.W.). Publisher Copyright: {\textcopyright} 2018, The Author(s).",

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doi = "10.1038/s41467-018-07258-y",

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Liu, J, Duan, Z, Guo, W, Zeng, L, Wu, Y, Chen, Y, Tai, F, Wang, Y, Lin, Y, Zhang, Q, He, Y, Deng, J, Stewart, RL, Wang, C, Lin, PC, Ghaffari, S, Evers, BM, Liu, S, Zhou, MM, Zhou, BP & Shi, J 2018, 'Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer', Nature Communications, vol. 9, no. 1, 5200. https://doi.org/10.1038/s41467-018-07258-y

TY - JOUR

T1 - Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer

AU - Liu, Jingyi

AU - Duan, Zhibing

AU - Guo, Weijie

AU - Zeng, Lei

AU - Wu, Yadi

AU - Chen, Yule

AU - Tai, Fang

AU - Wang, Yifan

AU - Lin, Yiwei

AU - Zhang, Qiang

AU - He, Yanling

AU - Deng, Jiong

AU - Stewart, Rachel L.

AU - Wang, Chi

AU - Lin, Pengnian Charles

AU - Ghaffari, Saghi

AU - Evers, B. Mark

AU - Liu, Suling

AU - Zhou, Ming Ming

AU - Zhou, Binhua P.

AU - Shi, Jian

N1 - Funding Information: We thank Dr. Claudia Scholl for providing CDK6 expression plasmid. We also thank Dr. Cathy Anthony for critical reading and editing of this manuscript. This research was supported by the Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558) and University of Kentucky Center of Biomedical Research Excellence in Cancer and Metabolism (P20 GM121327). This work was also supported by grants from NIH (CA125454 and CA188118 to B.P.Z., and CA87658 and CA203067 to M.M.Z.), and DoD (BC140733 to M.M.Z. and B.P.Z.). This work was also supported in part by National Natural Science Foundation of China (81672629 to J.S.; 81402434 to Y.W.; 81530075 and 81773155 to S.L.), Science and Technology Program of Guangzhou, China (201707010331 to J.S.), and Basic Public Welfare Research Program of Zhejiang Province (LGF18H290003 to Y.W.). Publisher Copyright: © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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VL - 9

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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