Co-inhibition of BET proteins and PI3Kα triggers mitochondrial apoptosis in rhabdomyosarcoma cells
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ABSTRACT:
PROVIDER: PRJNA607269 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11101378_1.fastq.gz | Fastqsanger.gz | |||
| SRR11101378_2.fastq.gz | Fastqsanger.gz | |||
| SRR11101379_1.fastq.gz | Fastqsanger.gz | |||
| SRR11101379_2.fastq.gz | Fastqsanger.gz | |||
| SRR11101380_1.fastq.gz | Fastqsanger.gz |
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Project description:Remodeling transcription by targeting bromodomain and extraterminal (BET) proteins has emerged as promising anticancer strategy. Here, we identify a novel synergistic interaction of the BET inhibitor JQ1 with the PI3Kα-specific inhibitor BYL719 to trigger mitochondrial apoptosis and to suppress tumor growth in models of rhabdomyosarcoma (RMS). RNA-Seq revealed that JQ1/BYL719 co-treatment shifts the overall balance of BCL-2 family gene expression towards apoptosis and upregulates expression of BMF, BCL2L11 (BIM) and PMAIP1 (NOXA) while downregulating BCL2L1 (BCL-xL).
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Project description:Bromodomain and Extra Terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic paradigm by directly targeting epigenetic readers1,2. Early clinical trials have shown significant promise especially in acute myeloid leukaemia (AML)3; therefore the evaluation of resistance mechanisms, an inevitable consequence of cancer therapies, is of utmost importance to optimise the clinical efficacy of these drugs. Using primary murine stem and progenitor cells immortalised with MLL-AF9, we have used an innovative approach to generate 20 cell lines derived from single cell clones demonstrating stable resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism but is demonstrated to emerge from leukaemia stem cells (LSC). Resistant clones display a leukaemic granulocyte-macrophage progenitor (L-GMP) phenotype (Lin-, Sca-, cKit+, CD34+, Fc³RII/RIII+) and functionally exhibit increased clonogenic capacity in vitro and markedly shorter leukaemia latency in vivo. Chromatin bound BRD4 is globally reduced in resistant cells, however expression of key target genes such as MYC remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors is in part a consequence of increased Wnt/²-catenin signaling. Negative regulation of this pathway results in differentiation of resistant cells into mature leukaemic blasts, inhibition of MYC expression and restoration of sensitivity to I-BET in vitro and in vivo. Finally, we show that the sensitivity of primary human AML cells to I-BET correlates with the baseline expression of Wnt/²-catenin target genes. Together these findings provide novel insights into the biology of AML, highlight the potential therapeutic limitations of BET inhibitors and identify strategies that may overcome resistance and enhance the clinical utility of these unique targeted therapies. Comparison of iBET resistant and sensitive cell lines
2015-09-15 | E-GEOD-63682 | biostudies-arrayexpress
Project description:Bromodomain and extraterminal proteins (BET) are epigenetic adaptors that play critical roles in gene regulation. This protein family contains two conserved bromodomains which can mediate the interaction with acetylated histone lysine residues and/or other acetylated proteins, and one extraterminal (ET) domain. BET protein inhibition has been recognized as a promising therapeutic strategy for several diseases, including acute myeloid leukaemia, castration resistant prostate cancer, and triple negative breast cancer. BET inhibition by a specific inhibitor JQ1 caused an impairment in various brain functions but the underlying molecular mechanisms are not well understood. Among BET family members, BRD4 has been recognized for its prominent role in epigenetic regulation of gene expression. However, we have found an extensive functional redundancy and coordination among all three major BET family members (BRD2/3/4) during the activity-dependent gene induction in neurons, which is also reflected in learning and memory behavior. Our study further revealed the molecular hierarchy in the coordination of BET family proteins dissecting their distinctive functions during gene induction required for proper brain function and plasticity. Understanding the functional coordination of BET family proteins at the molecular level would be beneficial to the development of more selective interventions for various diseases that are caused by dysregulated epigenetic pathways.
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Project description:Data independent acquisition (DIA) mass spectrometry was used to study the selectivity of 2J2V for BET proteins from A549 cells. BET proteins, BRD2, BRD3 and BRD4 were observed to be degraded the most by 2J2V in comparison to MZ1 or DMSO.
2024-10-08 | PXD049407 | Pride
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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
Project description:The objective was to identify the molecular mechanisms responsible for in vitro and in vivo efficacy of an anti-MYCN peptide nucleic acid on a preclinical model of alveolar rhabdomyosarcoma. Cells treated with a anti-MYCN PNA exhibit growth arrest and apoptosis, and in vivo tumor growth is blocked. Keywords: oncogene inhibition RH30 alveolar rhabdomyosarcoma cell line was treated with a 10uM concentration of anti-MYCN PNA or a mutated PNA devoid of any activity. After 12 hours RNA was extracted from untreated and treated cells and gene expression was analyzed by Affymetrix Gene Chips.
2011-12-31 | E-GEOD-7959 | biostudies-arrayexpress
Project description:Cellular metabolism exceedingly determines hematopoietic stem cells (HSCs) divisional fate and functioning through organelles interaction upon stress-induced response. The outer mitochondrial membrane-localized E3 ubiquitin ligase Mitol/Marchf5 (encoded by Mitol gene) is known to regulate mitochondrial and endoplasmic reticulum (ER) interaction and promote cell survival. To investigate the precise functional involvement of Mitol in HSC maintenance, we analyzed MX1-cre inducible Mitol knockout mice. Mitol deletion in bone marrow (BM) leads to HSCs exhaustion and impairment of BM reconstitution capability. Moreover, Mitol deletion induced prolonged ER stress in HSCs, which triggers cellular apoptosis that is mainly regulated by IRE1a signaling. Inhibition of ER stress by KIRA6 could partially reduce apoptosis of long term-HSC. Our observations indicated that Mitol is principal to maintain hematopoietic homeostasis and protects HSCs from apoptosis mainly through ER function via IRE1a signaling.
2023-12-18 | GSE240788 | GEO
Project description:Role of bromodomain and extra-terminal motif (BET) proteins in GATA1-null erythrolbasts (G1E) and in differentiation induced by activation of conditional GATA1 tested by addition of BET inhibitor JQ1 (250nM) Array protocols were conducted as described in the Ambion WT Expression Manual and the Affymetrix GeneChip Expression Analysis Technical Manual by the University of Pennsylvania Molecular Profiling Core. Two-factor design (+/- JQ1, +/- GATA1). External RNA spike-in controls (ERCC controls, Ambion) added to each sample in proportion to cell number at the time of RNA harvest.
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