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

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74 Citations (SciVal)

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

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

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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",

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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

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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

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.

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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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