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

Proc Natl Acad Sci U S A. 2018 May 29;115(22):E5086-E5095. doi: 10.1073/pnas.1712363115. Epub 2018 May 15.

Authors

Liang Xu¹, Ye Chen², Anand Mayakonda², Lynnette Koh^{3

4}, Yuk Kien Chong³, Dennis L Buckley⁵, Edwin Sandanaraj^{3

4

6}, See Wee Lim³, Ruby Yu-Tong Lin², Xin-Yu Ke², Mo-Li Huang^{2

7}, Jianxiang Chen⁸, Wendi Sun⁴, Ling-Zhi Wang^{2

9}, Boon Cher Goh^{2

9

10}, Huy Q Dinh¹¹, Dennis Kappei², Georg E Winter⁵, Ling-Wen Ding², Beng Ti Ang^{6

12

13

14}, Benjamin P Berman¹¹, James E Bradner^{5

15}, Carol Tang^{3

8

13}, H Phillip Koeffler^{2

10

16}

Affiliations

¹ Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore; csixl@nus.edu.sg.
² Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore.
³ Department of Research, National Neuroscience Institute, 308433 Singapore.
⁴ School of Biological Sciences, Nanyang Technological University, 637551 Singapore.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
⁶ Singapore Institute for Clinical Sciences, Agency for Science, Technology, and Research, 117609 Singapore.
⁷ School of Biology and Basic Medical Sciences, Soochow University, 215123 Suzhou, China.
⁸ Humphrey Oei Institute of Cancer Research, National Cancer Centre, 169610 Singapore.
⁹ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600 Singapore.
¹⁰ National University Cancer Institute, National University Hospital, 119074 Singapore.
¹¹ Center for Bioinformatics and Functional Genomics, Biomedical Sciences, Cedars-Sinai Medical Center, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90048.
¹² Department of Neurosurgery, National Neuroscience Institute, 308433 Singapore.
¹³ Duke-National University of Singapore Medical School, 169857 Singapore.
¹⁴ Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117593 Singapore.
¹⁵ Department of Medicine, Harvard Medical School, Boston, MA 02115.
¹⁶ Division of Hematology/Oncology, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Cell Cycle Proteins
Cell Line, Tumor
Drug Delivery Systems
E2F1 Transcription Factor* / antagonists & inhibitors
E2F1 Transcription Factor* / metabolism
Gene Expression Regulation, Neoplastic / drug effects
Glioblastoma* / metabolism
Glioblastoma* / pathology
Humans
Nuclear Proteins / antagonists & inhibitors
Nuclear Proteins / metabolism
Protein Domains
Protein Serine-Threonine Kinases* / antagonists & inhibitors
Protein Serine-Threonine Kinases* / metabolism
RNA-Binding Proteins* / antagonists & inhibitors
RNA-Binding Proteins* / metabolism
Transcription Factors / antagonists & inhibitors
Transcription Factors / metabolism

Substances

Antineoplastic Agents
BRD2 protein, human
BRD3 protein, human
BRD4 protein, human
BRDT protein, human
Cell Cycle Proteins
E2F1 Transcription Factor
E2F1 protein, human
Nuclear Proteins
RNA-Binding Proteins
Transcription Factors
Protein Serine-Threonine Kinases