BET inhibitors repress expression of interferon-stimulated genes and synergize with HDAC inhibitors in glioblastoma.

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Version: author
License: CC BY-NC 4.0
Serval ID
serval:BIB_925836B89EDF
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
BET inhibitors repress expression of interferon-stimulated genes and synergize with HDAC inhibitors in glioblastoma.
Journal
Neuro-oncology
Author(s)
Gusyatiner O., Bady P., Pham MDT, Lei Y., Park J., Daniel R.T., Delorenzi M., Hegi M.E.
ISSN
1523-5866 (Electronic)
ISSN-L
1522-8517
Publication state
Published
Issued date
01/10/2021
Peer-reviewed
Oui
Volume
23
Number
10
Pages
1680-1692
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
The development of rational combination therapies is key to overcome inherent treatment resistance of glioblastoma (GBM). We aim at identifying new druggable targets by disturbing GBM cells with inhibitors of bromodomain and extra-terminal motif (BET) proteins to reveal cancer-relevant vulnerabilities that may sensitize to a second drug. BET proteins are epigenetic modulators and have been associated with proto-oncogene overexpression in cancer.
A GBM-derived sphere-line was treated with the BET inhibitor (BETi) JQ1 over a time-course of 48 hours, followed by RNA-sequencing. Four chromatin marks were investigated by chromatin immunoprecipitation followed by sequencing (ChIP-seq). Signatures of interest were functionally validated in vitro and in orthotopic xenografts. Combination therapies were evaluated for synergistic effects.
Cancer-relevant pathways significantly modulated by JQ1 comprised interferon alpha (IFN-α) response genes and response signatures to histone deacetylase inhibitors (HDACi). The IFN-signature was reminiscent of a GBM-derived IFN-signature comprising CD274 (PD-L1). Functional pathway analysis suggested that JQ1 was acting directly on the transcriptional level of IFN-response genes and not via the canonical JAK/STAT pathway. This was in line with JQ1 modulated expression and BRD4 and Pol II occupancy at IFN-signature genes, supporting a direct mechanistic interaction. Finally, we showed that combining HDACi with JQ1 acts synergistically in reducing cell viability of GS-lines.
Our approach identified BETi-induced vulnerabilities in cancer-relevant pathways, potentially amenable to synergistic combinatorial therapy, such as combination with HDACi. The direct inhibitory effect of BETi on IFN-responsive genes in GBM cells, including CD274, indicates modulation of the tumor immune landscape and warrants further studies.
Keywords
Glioblastoma/drug therapy, Glioblastoma/genetics, Histone Deacetylase Inhibitors/pharmacology, Humans, Interferons, Nuclear Proteins, BET inhibitors, epigenetics, glioblastoma, interferon-stimulated genes, synergistic combination therapy
Pubmed
Web of science
Open Access
Yes
Funding(s)
Swiss National Science Foundation / Projects / 31003A_182821
Other / Swiss cancer research, KFS-4461-02-2018)
Swiss National Science Foundation / 31003A_163297
Create date
29/05/2021 15:18
Last modification date
23/07/2022 6:11
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