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EGR1 induction compromises the therapeutic efficacy of BET depletion in triple-negative breast cancer (ChIP-Seq)

ABSTRACT: Bromodomain and extraterminal domain (BET) proteins are epigenetic readers of acetylated lysine residues, which regulate gene expression and are involved in tumorigenesis. Over the past two decades, BET-bromodomain (BD) inhibitors and BET-targeting PROTAC degraders have been developed and clinically tested. BET protein depletion with PROTAC degrader is generally recognized to provide stronger outcomes compared to just inhibiting the binding of protein to acetylated lysine residues with competitive inhibitors. In this study, we found that the bivalent BET-BD inhibitor MS645 exhibited much more potent anti-proliferative activity than BET degraders, including ARV771, AT1, MZ1 and dBET1 in triple-negative breast cancer cells. MS645 treatment dissociated BET proteins from chromatin and decreased E2F1-3 expression, thus inhibited cell growth of TNBC. While ARV771 treatment didn't affect E2F1-3 expression though it displaced BET proteins from chromatin as well. We found knockdown of BRD4 or BRD4 depletion by ARV771 treatment dramatically induced EGR1 expression. EGR1 interacts with Septin complex and maintained its nuclear distribution. Septin complex is recruited by EGR1 to E2F1-3 gene loci to activate E2F1-3 transcription, thus maintained cell cycle progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246320 | GEO | 2025/10/31

REPOSITORIES: GEO

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EGR1 induction compromises the therapeutic efficacy of BET depletion in triple-negative breast cancer (RNA-Seq)

Project description:Bromodomain and extraterminal domain (BET) proteins are epigenetic readers of acetylated lysine residues, which regulate gene expression and are involved in tumorigenesis. Over the past two decades, BET-bromodomain (BD) inhibitors and BET-targeting PROTAC degraders have been developed and clinically tested. BET protein depletion with PROTAC degrader is generally recognized to provide stronger outcomes compared to just inhibiting the binding of protein to acetylated lysine residues with competitive inhibitors. In this study, we found that the bivalent BET-BD inhibitor MS645 exhibited much more potent anti-proliferative activity than BET degraders, including ARV771, AT1, MZ1 and dBET1 in triple-negative breast cancer cells. MS645 treatment dissociated BET proteins from chromatin and decreased E2F1-3 expression, thus inhibited cell growth of TNBC. While ARV771 treatment didn't affect E2F1-3 expression though it displaced BET proteins from chromatin as well. We found knockdown of BRD4 or BRD4 depletion by ARV771 treatment dramatically induced EGR1 expression. EGR1 interacts with Septin complex and maintained its nuclear distribution. Septin complex is recruited by EGR1 to E2F1-3 gene loci to activate E2F1-3 transcription, thus maintained cell cycle progression.

2025-10-31 | GSE246319 | GEO

Acute loss of BRD4 halts global transcriptional elongation and collapses the core regulatory circuitry of acute lymphoblastic leukemia [RNA-Seq]

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2016-04-01 | E-GEOD-79253 | biostudies-arrayexpress

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Project description:Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins which undermines the growth and survival of AML cells. However, BETi treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4, which potentially compromises the activity of BETi in AML cells. Unlike BETi, BET-PROTAC (proteolysis-targeting chimera) ARV-825 recruits and utilize an E3-ubiquitin ligase to effectively degrade BETPs in AML cells. BET-PROTACs induce more apoptosis than BETi of mtRUNX1 AML cells. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi. It was noted that treatment with BETi or BET-PROTAC caused significant and sustained depletion of RUNX1 in AML cells. We also determined the effects of global depletion of RUNX1 in mtRUNX1 expressing AML OCI-AML5 cells. We observed an overlap in the signature of RUNX1 knockdown by shRNA with that of OTX015 and ARV-825 in OCI-AML5 cells.

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Novel BET protein Proteolysis Targeting Chimera (BET-PROTAC) exerts superior lethal activity than Bromodomain Inhibitor (BETi) against post-myeloproliferative Neoplasm (MPN) Secondary (s) AML Cells

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Small-molecule inhibitor JQ1 effect on multiple myeloma cell lines

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2011-09-01 | E-GEOD-31365 | biostudies-arrayexpress

Functions of BET proteins in GATA1-mediated transcription [ChIP-seq]

Project description:Transcription factor GATA1 binding in erythroblasts in the presence and absence of BET inhibitor JQ1, and BET protein BRD3 and BRD4 binding in erythroblasts in the presence and absence of GATA1. Inhibitors of Bromodomain and Extra-Terminal motif proteins (BETs) are being evaluated for the treatment of cancer and other diseases yet their physiologic mechanisms remain largely unknown. We used genomic and genetic approaches to examine BET function in a hematopoietic maturation system driven by GATA1, an acetylated transcription factor previously shown to interact with BETs. We found that while BRD3 occupied the majority of GATA1 binding sites, BRD2 and BRD4 were also recruited to a subset of GATA1-occupied sites. Functionally, BET inhibition impaired GATA1-mediated transcriptional activation, but not repression, genome-wide. Co-activation by BETs was accomplished both by facilitating genomic occupancy of GATA1 and subsequently supporting transcription activation. Using a combination of CRISPR/CAS9-mediated genomic engineering and shRNA approaches we observed that depletion of either BRD2 or BRD4 alone blunted erythroid gene activation, while depletion of BRD3 only affected erythroid transcription in the setting of BRD2 deficiency. These results suggest that pharmacologic BET inhibition should be interpreted in the context of distinct steps in transcriptional activation and partially overlapping functions among BET family members. GATA1 null erythroblasts (G1E) conditionally expressing GATA1 as a GATA1-ER fusion protein were induced to express GATA1 by addition of 100nM estradiol for 24 hours. For GATA1 binding experiments this occurred in the absence or presence of 250nM JQ1. For BRD3 and BRD4 occupancy experiments G1E cells were compared to G1E cells with activated GATA1-ER fusion protein.

2015-02-23 | E-GEOD-62736 | biostudies-arrayexpress

Hematopoietic transcription factors and p300/CBP shape the effects of BET bromodomain inhibition in leukemia [ChIP-Seq]

Project description:The bromodomain and extraterminal (BET) protein Brd4 is a validated drug target in leukemia, yet its regulatory function in this disease is not well understood. Here, we show that Brd4 chromatin occupancy in acute myeloid leukemia closely correlates with the hematopoietic transcription factors (TFs) Pu.1, Fli1, Erg, C/EBPα, C/EBPβ, and Myb at nucleosome-depleted enhancer and promoter regions. We provide evidence that these TFs, in conjunction with the lysine acetyltransferase activity of p300/CBP, facilitate Brd4 recruitment to their occupied sites to promote transcriptional activation. Moreover, chemical inhibition of BET bromodomains is found to suppress the functional output each hematopoietic TF, thereby interfering with essential lineage-specific transcriptional circuits in this disease. These findings reveal a chromatin-based signaling cascade comprised of hematopoietic TFs, p300/CBP, and Brd4, which supports leukemia maintenance and is suppressed by BET bromodomain inhibition. ChIP-Seq for regulatory factors of Brd4 in MLL-AF9 transformed acute myeloid leukemia cells (RN2)

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Response and resistance to BET bromodomain inhibitors in triple negative breast cancer [ChIP-Seq]

Project description:Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance. ChIP-seq in parental and JQ1 resistant triple negative breast cancer (TNBC) in response to DMSO or JQ1 treatment

2016-01-07 | E-GEOD-63581 | biostudies-arrayexpress

Response and resistance to BET bromodomain inhibitors in triple negative breast cancer [Chem-Seq]

Project description:Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance. Chem-Seq in parental and JQ1 resistant triple negative breast cancer (TNBC)

2016-01-07 | E-GEOD-63284 | biostudies-arrayexpress

Depletion of BRD9-mediated R-loop accumulation inhibits leukemia cell growth via transcription-replication conflict

Project description:Bromodomain-containing protein 9 (BRD9) has emerged as a promising therapeutic target for blood cancers, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM). PROTAC-based BRD9 degraders effectively hamper the growth and survival of leukemia cells; however, the underlying mechanism of these BRD9 degraders remains unclear. In this study, we demonstrated that depletion of BRD9 triggers DNA damage via R-loop accumulation, leading to conflicts between transcription and replication processes. Replication stress inhibits the proliferation of leukemia cells and promotes their differentiation. Mechanistically, BRD9 plays a pivotal role in recruiting BRD2 and BRD4 to chromatin through direct interactions, which is critical for preventing R-loop formation during transcription. Depletion of BRD9 in leukemia cells reduces the occupancy of BRD2 and BRD4 at R-loop-prone sites, thus promoting R-loop accumulation, transcription-replication collision, excessive DNA damage, and ultimately, the demise of cancer cells. These findings provide valuable insights into the mechanisms by which BRD9 degraders function as effective therapies for leukemia mediated by the pathological accumulation of R-loops.

2025-07-16 | GSE300622 | GEO

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