Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma

Liang Xu; Ye Chen; Anand Mayakonda; Lynnette Koh; Yuk Kien Chong; Dennis L. Buckley; Edwin Sandanaraj; See Wee Lim; Ruby Yu Tong Lin; Xin Yu Ke; Mo Li Huang; Jianxiang Chen; Wendi Sun; Ling Zhi Wang; Boon Cher Goh; Huy Q. Dinh; Dennis Kappei; Georg E. Winter; Ling Wen Ding; Beng Ti Ang; Benjamin P. Berman; James E. Bradner; Carol Tang; H. Phillip Koeffler

doi:10.1073/pnas.1712363115

Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma

Liang Xu^*, Ye Chen, Anand Mayakonda, Lynnette Koh, Yuk Kien Chong, Dennis L. Buckley, Edwin Sandanaraj, See Wee Lim, Ruby Yu Tong Lin, Xin Yu Ke, Mo Li Huang, Jianxiang Chen, Wendi Sun, Ling Zhi Wang, Boon Cher Goh, Huy Q. Dinh, Dennis Kappei, Georg E. Winter, Ling Wen Ding, Beng Ti AngBenjamin P. Berman, James E. Bradner, Carol Tang, H. Phillip Koeffler

^*Corresponding author for this work

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

64 Scopus citations

Abstract

Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM.

Original language	American English
Pages (from-to)	E5086-E5095
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	115
Issue number	22
DOIs	https://doi.org/10.1073/pnas.1712363115
State	Published - 29 May 2018
Externally published	Yes

Bibliographical note

Funding Information:
We thank Nathanael S. Gray, Jinhua Wang, Tinghu Zhang, Lavina Tay, Shwu-Yuan Wu, and Cheng-Ming Chiang for reagent sharing; and Hazimah Binte Mohd Nordin for help with mouse work. We are grateful to Bing Ren, Sudhakar Jha, Fang Hu, and members of the H.P.K. laboratory for kind discussions and suggestions. This work is funded by the National Research Foundation Singapore under the Singapore Translational Research Investigator Award NMRC/STaR/0021/2014 (to H.P.K.); the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2013-T2-2-150 and MOE2017-T2-1-033); the Singapore Ministry of Health’s National Medical Research Council (NMRC) Centre Grant awarded to National University Cancer Institute of Singapore (NCIS), the National Research Foundation Singapore, and the Singapore Ministry of Education under its Research Cen-tres of Excellence initiatives; and is additionally supported by a Seed Funding Program within the NCIS Centre Grant, an NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust and philanthropic donations from the Melamed family, Aaron Eshman, and Valerie Baker Fair-bank who deeply inspires our work. B.T.A. and C.T. are supported by an NMRC Translational & Clinical Research Flagship Programme Grant (NMRC/ TCR/016-NNI/2016). D.L.B. was supported by the Damon Runyon Cancer Research Foundation as a Merck Fellow (DRG-2196-14). The computational work for this article was partially performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg).

Funding Information:
ACKNOWLEDGMENTS. We thank Nathanael S. Gray, Jinhua Wang, Tinghu Zhang, Lavina Tay, Shwu-Yuan Wu, and Cheng-Ming Chiang for reagent sharing; and Hazimah Binte Mohd Nordin for help with mouse work. We are grateful to Bing Ren, Sudhakar Jha, Fang Hu, and members of the H.P.K. laboratory for kind discussions and suggestions. This work is funded by the National Research Foundation Singapore under the Singapore Translational Research Investigator Award NMRC/STaR/0021/2014 (to H.P.K.); the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2013-T2-2-150 and MOE2017-T2-1-033); the Singapore Ministry of Health’s National Medical Research Council (NMRC) Centre Grant awarded to National University Cancer Institute of Singapore (NCIS), the National Research Foundation Singapore, and the Singapore Ministry of Education under its Research Centres of Excellence initiatives; and is additionally supported by a Seed Funding Program within the NCIS Centre Grant, an NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust and philanthropic donations from the Melamed family, Aaron Eshman, and Valerie Baker Fair-bank who deeply inspires our work. B.T.A. and C.T. are supported by an NMRC Translational & Clinical Research Flagship Programme Grant (NMRC/ TCR/016-NNI/2016). D.L.B. was supported by the Damon Runyon Cancer Research Foundation as a Merck Fellow (DRG-2196-14). The computational work for this article was partially performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg).

Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.

Keywords

BRD2
BRD3
BRD4
E2F
Glioma

UN SDGs

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

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10.1073/pnas.1712363115

Cite this

Xu, L., Chen, Y., Mayakonda, A., Koh, L., Chong, Y. K., Buckley, D. L., Sandanaraj, E., Lim, S. W., Lin, R. Y. T., Ke, X. Y., Huang, M. L., Chen, J., Sun, W., Wang, L. Z., Goh, B. C., Dinh, H. Q., Kappei, D., Winter, G. E., Ding, L. W., ... Koeffler, H. P. (2018). Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma. Proceedings of the National Academy of Sciences of the United States of America, 115(22), E5086-E5095. https://doi.org/10.1073/pnas.1712363115

@article{83fd7193833a4570a81dfdbc8eff79ec,

title = "Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma",

abstract = "Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM.",

keywords = "BRD2, BRD3, BRD4, E2F, Glioma",

author = "Liang Xu and Ye Chen and Anand Mayakonda and Lynnette Koh and Chong, {Yuk Kien} and Buckley, {Dennis L.} and Edwin Sandanaraj and Lim, {See Wee} and Lin, {Ruby Yu Tong} and Ke, {Xin Yu} and Huang, {Mo Li} and Jianxiang Chen and Wendi Sun and Wang, {Ling Zhi} and Goh, {Boon Cher} and Dinh, {Huy Q.} and Dennis Kappei and Winter, {Georg E.} and Ding, {Ling Wen} and Ang, {Beng Ti} and Berman, {Benjamin P.} and Bradner, {James E.} and Carol Tang and Koeffler, {H. Phillip}",

note = "Funding Information: We thank Nathanael S. Gray, Jinhua Wang, Tinghu Zhang, Lavina Tay, Shwu-Yuan Wu, and Cheng-Ming Chiang for reagent sharing; and Hazimah Binte Mohd Nordin for help with mouse work. We are grateful to Bing Ren, Sudhakar Jha, Fang Hu, and members of the H.P.K. laboratory for kind discussions and suggestions. This work is funded by the National Research Foundation Singapore under the Singapore Translational Research Investigator Award NMRC/STaR/0021/2014 (to H.P.K.); the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2013-T2-2-150 and MOE2017-T2-1-033); the Singapore Ministry of Health{\textquoteright}s National Medical Research Council (NMRC) Centre Grant awarded to National University Cancer Institute of Singapore (NCIS), the National Research Foundation Singapore, and the Singapore Ministry of Education under its Research Cen-tres of Excellence initiatives; and is additionally supported by a Seed Funding Program within the NCIS Centre Grant, an NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust and philanthropic donations from the Melamed family, Aaron Eshman, and Valerie Baker Fair-bank who deeply inspires our work. B.T.A. and C.T. are supported by an NMRC Translational & Clinical Research Flagship Programme Grant (NMRC/ TCR/016-NNI/2016). D.L.B. was supported by the Damon Runyon Cancer Research Foundation as a Merck Fellow (DRG-2196-14). The computational work for this article was partially performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg). Funding Information: ACKNOWLEDGMENTS. We thank Nathanael S. Gray, Jinhua Wang, Tinghu Zhang, Lavina Tay, Shwu-Yuan Wu, and Cheng-Ming Chiang for reagent sharing; and Hazimah Binte Mohd Nordin for help with mouse work. We are grateful to Bing Ren, Sudhakar Jha, Fang Hu, and members of the H.P.K. laboratory for kind discussions and suggestions. This work is funded by the National Research Foundation Singapore under the Singapore Translational Research Investigator Award NMRC/STaR/0021/2014 (to H.P.K.); the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2013-T2-2-150 and MOE2017-T2-1-033); the Singapore Ministry of Health{\textquoteright}s National Medical Research Council (NMRC) Centre Grant awarded to National University Cancer Institute of Singapore (NCIS), the National Research Foundation Singapore, and the Singapore Ministry of Education under its Research Centres of Excellence initiatives; and is additionally supported by a Seed Funding Program within the NCIS Centre Grant, an NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust and philanthropic donations from the Melamed family, Aaron Eshman, and Valerie Baker Fair-bank who deeply inspires our work. B.T.A. and C.T. are supported by an NMRC Translational & Clinical Research Flagship Programme Grant (NMRC/ TCR/016-NNI/2016). D.L.B. was supported by the Damon Runyon Cancer Research Foundation as a Merck Fellow (DRG-2196-14). The computational work for this article was partially performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg). Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All Rights Reserved.",

year = "2018",

month = may,

day = "29",

doi = "10.1073/pnas.1712363115",

language = "American English",

volume = "115",

pages = "E5086--E5095",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "22",

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Xu, L, Chen, Y, Mayakonda, A, Koh, L, Chong, YK, Buckley, DL, Sandanaraj, E, Lim, SW, Lin, RYT, Ke, XY, Huang, ML, Chen, J, Sun, W, Wang, LZ, Goh, BC, Dinh, HQ, Kappei, D, Winter, GE, Ding, LW, Ang, BT, Berman, BP, Bradner, JE, Tang, C & Koeffler, HP 2018, 'Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 22, pp. E5086-E5095. https://doi.org/10.1073/pnas.1712363115

TY - JOUR

T1 - Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma

AU - Xu, Liang

AU - Chen, Ye

AU - Mayakonda, Anand

AU - Koh, Lynnette

AU - Chong, Yuk Kien

AU - Buckley, Dennis L.

AU - Sandanaraj, Edwin

AU - Lim, See Wee

AU - Lin, Ruby Yu Tong

AU - Ke, Xin Yu

AU - Huang, Mo Li

AU - Chen, Jianxiang

AU - Sun, Wendi

AU - Wang, Ling Zhi

AU - Goh, Boon Cher

AU - Dinh, Huy Q.

AU - Kappei, Dennis

AU - Winter, Georg E.

AU - Ding, Ling Wen

AU - Ang, Beng Ti

AU - Berman, Benjamin P.

AU - Bradner, James E.

AU - Tang, Carol

AU - Koeffler, H. Phillip

N1 - Funding Information: We thank Nathanael S. Gray, Jinhua Wang, Tinghu Zhang, Lavina Tay, Shwu-Yuan Wu, and Cheng-Ming Chiang for reagent sharing; and Hazimah Binte Mohd Nordin for help with mouse work. We are grateful to Bing Ren, Sudhakar Jha, Fang Hu, and members of the H.P.K. laboratory for kind discussions and suggestions. This work is funded by the National Research Foundation Singapore under the Singapore Translational Research Investigator Award NMRC/STaR/0021/2014 (to H.P.K.); the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2013-T2-2-150 and MOE2017-T2-1-033); the Singapore Ministry of Health’s National Medical Research Council (NMRC) Centre Grant awarded to National University Cancer Institute of Singapore (NCIS), the National Research Foundation Singapore, and the Singapore Ministry of Education under its Research Cen-tres of Excellence initiatives; and is additionally supported by a Seed Funding Program within the NCIS Centre Grant, an NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust and philanthropic donations from the Melamed family, Aaron Eshman, and Valerie Baker Fair-bank who deeply inspires our work. B.T.A. and C.T. are supported by an NMRC Translational & Clinical Research Flagship Programme Grant (NMRC/ TCR/016-NNI/2016). D.L.B. was supported by the Damon Runyon Cancer Research Foundation as a Merck Fellow (DRG-2196-14). The computational work for this article was partially performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg). Funding Information: ACKNOWLEDGMENTS. We thank Nathanael S. Gray, Jinhua Wang, Tinghu Zhang, Lavina Tay, Shwu-Yuan Wu, and Cheng-Ming Chiang for reagent sharing; and Hazimah Binte Mohd Nordin for help with mouse work. We are grateful to Bing Ren, Sudhakar Jha, Fang Hu, and members of the H.P.K. laboratory for kind discussions and suggestions. This work is funded by the National Research Foundation Singapore under the Singapore Translational Research Investigator Award NMRC/STaR/0021/2014 (to H.P.K.); the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2013-T2-2-150 and MOE2017-T2-1-033); the Singapore Ministry of Health’s National Medical Research Council (NMRC) Centre Grant awarded to National University Cancer Institute of Singapore (NCIS), the National Research Foundation Singapore, and the Singapore Ministry of Education under its Research Centres of Excellence initiatives; and is additionally supported by a Seed Funding Program within the NCIS Centre Grant, an NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust and philanthropic donations from the Melamed family, Aaron Eshman, and Valerie Baker Fair-bank who deeply inspires our work. B.T.A. and C.T. are supported by an NMRC Translational & Clinical Research Flagship Programme Grant (NMRC/ TCR/016-NNI/2016). D.L.B. was supported by the Damon Runyon Cancer Research Foundation as a Merck Fellow (DRG-2196-14). The computational work for this article was partially performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg). Publisher Copyright: © 2018 National Academy of Sciences. All Rights Reserved.

PY - 2018/5/29

Y1 - 2018/5/29

N2 - Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM.

AB - Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM.

KW - BRD2

KW - BRD3

KW - BRD4

KW - E2F

KW - Glioma

UR - http://www.scopus.com/inward/record.url?scp=85047899793&partnerID=8YFLogxK

U2 - 10.1073/pnas.1712363115

DO - 10.1073/pnas.1712363115

M3 - Article

C2 - 29764999

AN - SCOPUS:85047899793

SN - 0027-8424

VL - 115

SP - E5086-E5095

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 22

ER -

Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma

Abstract

Bibliographical note

Keywords

UN SDGs

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