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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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RNA-seq of human melanoma cancer cell line A375 treated with BET inhibitor JQ1 against untreated control

ABSTRACT: To set the relevance of BRD4 as repressor, we performed gene expression profile by RNA-seq in A375 treated with BETi JQ1 to identify potential BRD4 target genes.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Homo sapiens

SUBMITTER: federica torricelli

PROVIDER: E-MTAB-8649 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The apoptotic network and expression of BH3-containing proteins predict phenotypic response to BET bromodomain inhibitors

Project description:Small molecule inhibitors of the bromodomain and extraterminal (BET) family of proteins are in clinical trials for a variety of cancers, but patient selection strategies are limited. This is due in part to the heterogeneity of response following BET inhibition (BETi), which includes differentiation, senescence, and cell death in subsets of cancer cell lines. To elucidate the dominant features defining response to BETi, we carried out phenotypic and gene expression analysis of both treatment naÃ¯ve cell lines and engineered tolerant lines. We found that both de novo and acquired tolerance to BET inhibition are driven by the robustness of the apoptotic response and that genetic or pharmacological manipulation of the apoptotic signaling network can modify the phenotypic response to BETi. We further identify that ordered expression of the apoptotic genes BCL2, BCL2L1, and BAD significantly predicts response to BETi. Our findings highlight the role of the apoptotic network in response to BETi, providing a molecular basis for patient stratification and combination therapies. Gene expression profiling of A375 melanoma cells or NOMO-1 AML cells treated with DMSO or the BET inhibitor, CPI203. Also, gene expression profiling of the respective derived BETi-tolerant cells treated with DMSO or CPI203.

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Adaptation of the Kinome Promotes Resistance to BET Bromodomain Inhibitors in Ovarian Cancer

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Project description:MAP4K5 is serine/threonine protein kinase similar to yeast SPS1/STE20 kinase. MAP4K5 activates JNK in mammalian cells, which suggests a role in stress response. MAP4K5 is involved in immune functions. We used microarray to investigate genome-wide transcriptional change from MAP4K5 knockdown in A375 cells. Total RNA's from the A375 cells where MAP4K5 was stably knocked down by shRNA were analyzed. As a control, RNA's from A375 cells were also analyzed.

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Analysis of A375 and A375 clones that acquired resistance to GSK2118436 after treatment with GSK2118436 (GSK436), GSK1120212 (GSK212), or the combination of GSK2118436 and GSK1120212 for 24 hour

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Gene expression profile in A375 melanoma cells after 45 functionally important molecules were knocked down using siRNA

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Streptococcus anginosus promotes hepatocellular carcinoma progression and BET inhibitor resistance by inducing BRD4 lactylation

Project description:<p>Hepatocellular carcinoma (HCC) is a highly aggressive form of carcinoma with a poor prognosis. Diagnostic markers and potential therapeutic targets for HCC are urgently needed. Here, we demonstrate that fecal microbiota transplantation (FMT) using stool samples from HCC patients significantly promote the growth of patient-derived xenografts (PDXs). 16s-rRNA sequencing combined with qPCR reveal that Streptococcus anginosus (S. anginosus) is enriched in the stool samples of HCC patients and HCC-FMT mice. S. anginosus monocolonization recapitulates the tumor-promoting effect of HCC-FMT in germ-free (GF) mice. Mechanistically, S. anginosus plays a critical role in regulating the downstream pathways of BRD4 via its metabolites, thereby promoting the activation of oncogenic Myc and E2F signaling pathways, HCC progression and BET inhibitor (BETi) resistance. S. anginosus-derived lactate promotes BRD4 lactylation at the K317 site via AARS1, thereby inhibiting BRD4 ubiquitination and degradation. Notably, blockade of the S. anginosus-BRD4 lactylation axis improves the BETi responsiveness in both syngeneic mouse models and PDXs. Overall, our study highlights the oncogenic role of the S. anginosus-BRD4 signaling in the gut-liver axis and suggests its potential as a non-invasive biomarker and therapeutic target for HCC.</p>

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A375 melanoma cells treated with leflunomide 25uM

Project description:Human A375 melanoma cells were treated with leflunomide 25uM for 3 days, then RNA harvested 6 arrays

2011-03-30 | E-GEOD-24526 | biostudies-arrayexpress

Chromatin occupancy of key transcriptional regulators in the presence of the BET bromodomain inhibitor JQ1

Project description:MM1.S cells are an aggressive dexamethasone sensitive multiple myeloma cell line whose transcritional program is driven by deregulated c-Myc activity. We present ChIP-seq analysis of key transcritional regulators that are implicated the c-Myc transcriptional network in MM1.S cells treated with vehicle or 500nM JQ1. Brd4, Cdk9, cMyc, Max, Med1, RNA Pol II, and the chromatin modifications H3K4me3 and H3K27Ac were profiled in MM1.S cells treated with 500nM JQ1 for 24hr

2012-11-30 | E-GEOD-42161 | biostudies-arrayexpress

BRD4 loading at the transcription start site mediates pause-release and underlies the disproportionate transcriptional response to BET bromodomain inhibition [GRO-Seq]

Project description:BET bromodomain inhibition (BETi) abrogates cancer cell growth by disrupting oncogenic gene expression. BRD4 loading at enhancers has been suggested to mediate pause-release and underlie the selective transcriptional response to BETi. Here, we utilized GRO-seq coupled with ChIP-seq to assess the association between gene control elements and the transcriptional response to BETi. Genes immediately down-regulated by BETi display a marked pause-release defect with a minimal impact on transcript elongation within the gene body. Surprisingly, we find that BRD4 at super-enhancers does not render its associated genes or enhancer RNAs preferentially sensitive to BETi. In contrast, disproportionate loading of BRD4 at transcription start sites (TSS) correlates with the transcriptional response to BETi. Moreover, BRD4 loading at TSSs, but not enhancers, is associated with enhanced promoter-proximal pausing following BETi. Our findings stress a mechanistic role of promoter-associated BRD4 in pause-release and suggest that BRD4 loading at the TSS drives the selective transcriptional response to BETi.

2023-01-06 | GSE70449 | GEO

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