Gene expression profiling data following TRIM8 knockdown in MCF-7 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE157109 | GEO | 2020/08/29
REPOSITORIES: GEO
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Project description:We recently described TRIM8, a nuclear E3 ubiquitin ligase, whose expression inversely correlates with glioma grade. TRIM8 restoration suppresses cell growth and induces a significant reduction of clonogenic potential in both U87MG glioblastoma and patients’ primary glioma cell lines. Since E3 ubiquitin ligase proteins regulate carcinogenesis through the timely control of many cellular processes such as DNA damage response, metabolism, transcription, and apoptosis, we reasoned that TRIM8 activity might impact on cell transcriptome patterns, thereby promoting cancer development and progression. Therefore, we profiled the whole transcriptome of normal embryonic neural stem cells (eNSC) infected with a retrovirus expressing FLAG-Trim8 by using RNA-Seq. RNA-Seq revealed 1365 differentially expressed transcripts of 912 genes. 723 of them (corresponding to 648 RefSeq genes) differed significantly of at least 1.5 folds (192 upregulated transcripts of 178 genes and 531 downregulated transcripts of 470 genes). 80 genes, among all differentially expressed genes, resulted to significantly enrich 18 pathways by IPA analysis. 53% of these genes (43 out of 80 genes) are related to cell-morphology, cell death and survival, with a preponderantly representation of signaling pathways related to neurotransmission and to CNS, including axonal guidance, GABA Receptor, ephrin B, synaptic long-term potentiation/depression, and glutamate receptor. Specifically, our results substantiate the role of TRIM8 in the brain functions through the dysregulation of genes involved in different pathways, including JAK-STAT. Finally, we provided additional evidence about the existence of a functional interactive crosstalk between TRIM8 and STAT3 with possible implications in the development and progression of glioma.
2018-04-07 | GSE112810 | GEO
Project description:Fusion-transcription factors (fusion-TFs) represent a class of driver oncoproteins that are difficult to therapeutically target. Recently, protein degradation has emerged as a strategy to target these challenging oncoproteins. The mechanisms that regulate fusion-TF stability, however, are generally unknown. Using CRISPR-Cas9 screening, we discovered tripartite motif- containing 8 (TRIM8) as an E3 ubiquitin ligase that ubiquitinates and degrades EWS/FLI, a driver fusion-TF in Ewing sarcoma. Moreover, we identified TRIM8 as a selective dependency in Ewing sarcoma compared to >700 other cancer cell lines. Mechanistically, TRIM8 knockout led to an increase in EWS/FLI protein levels that was not tolerated. EWS/FLI acts as a neomorphic substrate for TRIM8, defining the selective nature of the dependency. Our results demonstrate that fusion-TF protein stability is tightly regulated and highlight fusion-oncoprotein specific regulators as selective therapeutic targets. This study provides a tractable strategy to therapeutically exploit oncogene overdose in Ewing sarcoma and potentially other fusion-TF driven cancers.
2021-06-30 | GSE150244 | GEO
Project description:Estrogen Receptor alpha (ERα) is a ligand-inducible transcription factor that mediates estrogen signaling in hormone-responsive breast cancer (BC) and is the primary target of specific anticancer therapies that although effective can generate resistance phenomena that represents a crucial problem in clinical management of patients affected by this disease. DOT1 Like Histone Lysine Methyltransferase (DOT1L) and Menin 1 (MEN1) have been identified as functional component of the ERα mechanism of action. To investigate the involvement of DOT1L and MEN1 in mediating ERα actions in hormone-responsive and endocrine-resistant BC, interaction proteomics was applied to map the DOT1l and MEN1 nuclear interacting partners in MCF7 breast cancer cell nuclei in order to the identifiy new possible therapeutic targets for a more effective pharmacological treatment of endocrine therapy-resistant tumors.
2022-08-12 | PXD026864 | Pride
Project description:Estrogen Receptor αlpha (ERα) is the master regulator of estrogen signaling in hormone-responsive breast cancer (BC), however epigenetic mechanisms, including DNA methylation, are emerging as key processes for regulation of critical cell functions including tumorigenesis. We have recently reported the epigenetic writer DOT1L (DOT1 Like Histone Lysine Methyltransferase) to associated to ERα, part of chromatin bound multiprotein complex and that the pharmacological inhibition of this enzyme reduces the transcription rate of several genes involved in ERα-mediated signaling leading to inhibition of BC cell proliferation. Here, we investigated the functional impact of DOT1L inhibition on methylome changes in BC and its possible contribution to deregulation of transcriptional pathways associated to the progression of this disease.
2023-02-21 | E-MTAB-12635 | biostudies-arrayexpress
Project description:Estrogen Receptor alpha (ERα) is a ligand-inducible transcription factor that mediates estrogen signaling in hormone-responsive breast cancer (BC) and is the primary target of specific anticancer therapies. Although ERα blockade with these drugs is effective, the development of a resistance to treatment represents the key problem in clinical management of patients affected by this disease. Understanding the molecular mechanisms underlying ERα action in BC cells may help the identification of new therapeutic targets for more effective pharmacological treatment of endocrine therapy-resistant tumors. We recently discovered the epigenetic enzyme DOT1L (DOT1 Like Histone Lysine Methyltransferase) as a novel nuclear partner of ERα in BC cells. To investigate the involvement of DOT1L in mediating ERα actions in hormone-responsive and endocrine-resistant BC, physical and functional interaction between these two molecules on chromatin was mapped by Chromatin Immunoprecipitation coupled to Mass Spectrometry (ChIP-MS).
2019-02-09 | PXD010314 | Pride
Project description:To investigate the molecular mechanisms by which estrogen receptor α (ERα) inhibits type I IFN-induced signaling. We identified genes induced by ERα signaling using data obtained from RNA-seq of MCF7 cells treated or untreated with selective ERα agonist propyl pyrazole triol (PPT).
2022-05-18 | GSE203058 | GEO
Project description:Estrogen signaling plays important roles in diverse physiological and pathophysiological processes. However, the relationship between estrogen signaling and epigenetic regulation is not fully understood. Here, we explored the effect of estrogen signaling on the expression of Ten-Eleven Translocation (TET) family genes and DNA hydroxylmethylation in estrogen receptor alpha positive (ERα+) breast cancer cells. By analyzing the RNA-seq data, we identified TET2 as an estradiol (E2)-responsive gene in ERα+ MCF7 cells. RT-qPCR and Western blot analyses confirmed that both the mRNA and protein levels of TET2 gene were upregulated in MCF7 cells by E2 treatment. ChIP-seq and qPCR analyses showed that the enrichment of ERα and H3K27ac on the upstream regulatory regions of TET2 gene was increased in MCF7 cells upon E2 treatment. Moreover, E2 treatment also led to a significant increase in the global 5-hydroxymethylcytosine (5hmC) level, while knockout of TET2 abolished such E2-induced 5hmC increase. Conversely, treatment with ICI 182780, a potent and selective estrogen receptor degrader (SERD), inhibited TET2 gene expression and down-regulated the 5hmC level in MCF7 cells. Taken together, our study identified an ERα/TET2/5hmC epigenetic pathway, which may participate in the estrogen-associated physiological and pathophysiological processes.
2021-11-28 | GSE189507 | GEO
Project description:Endocrine therapies targeting the proliferative effect of 17β-estradiol (17βE2) through estrogen receptor α (ERα) are the most effective systemic treatment of ERα-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through a molecular mechanism that is not yet fully understood. The long-term estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors (AIs) in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERα. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were influenced by transcription factors known to be involved in acquired resistance or cell proliferation (e.g. IRF1 and E2F1, respectively) but, notably, not by canonical ERα transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)- to pS167-ERα were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERα-negative status, early response to letrozole and recurrence after tamoxifen treatment. This study proposes a mechanism for acquired resistance to estrogen deprivation that is coordinated across biological levels and independent of canonical ERα function. LTED (long term estrogen deprived) cell line was generated from MCF-7 cells by long-term culture under estrogen deprivated conditions. And RNA samples were obtained after 3, 15, 30, 90, 120, 150 and 180 days.
2010-09-01 | E-GEOD-20361 | biostudies-arrayexpress
Project description:Abstract Several endocrine therapy (ET) resistance mechanisms for ER-positive (ER+) breast cancer (BC) have been proposed, including acquired ESR1 (ERα gene) mutations. The two most common ESR1 mutations are Y537S and D538G, which give rise to a constitutively active receptor with reduced affinity for agonists and antagonists. The discovery of new effective therapies remains a significant challenge in treating mutated ER+ BC. In this context, Poly (ADP-ribose) polymerase-1 (PARP-1) has captured considerable interest as a target for therapeutic inhibitors in specific types of cancers. Here, we report that crosstalk between PARP-1 and ERα may represent a novel therapeutic approach for ER+ BC. We have demonstrated that the up-regulation of PARP-1 expression, stimulated by 17-β estradiol (E2), was blocked by treatment with fulvestrant (Ful), a potent ERα antagonist, or ESR1 siRNA in ER+ MCF7 and T47D BC cell models that express both wild type ERα and the Y537S mutation, indicating that ERα regulates the expression of PARP-1. In addition, ERα-mediated transcriptional activity depended on PARP-1 activity in these models, as confirmed by ERα target gene expression and ERE reporter gene analyses +/- niraparib (Nira). Notably, PARP-1 modulates the estrogen-dependent genomic binding of ERα and FoxA1, which play a crucial role in the proliferation of ER+ BC. We also showed that PARP-1 inhibition prevented proliferation and cell cycle activities of ERα WT and ERα Y537S cells upon ERα activation. In vivo, Nira and lasofoxifene (Laso), an ERα antagonist, significantly reduced primary tumor growth versus vehicle, both as single agents and in combination. Moreover, RNA-seq analyses demonstrated the downregulation of ERα signaling in the mammary glands of mice treated with Nira versus Vehicle. Our results provide novel insights into the molecular events through which PARP-1 may serve as a more comprehensive therapeutic approach to target ET BC resistance in women with advanced ER+ BC.
2024-09-30 | GSE277883 | GEO
Project description:The Estrogen Receptor alpha (ERα) controls key cellular functions in hormone responsive breast cancer by assembling in large functional multiprotein complexes. ERα ligands are classified as agonists and antagonist, according to the response they elicit, thus the molecular characterization of the of ERα nuclear iteractome composition following estrogen and antiestrogen stimulation whose is needed to understand their effects on estrogen target tissues, in particular breast cancer. To this aim interaction proteomics coupled to mass spectrometry (MS) was applied to map the ERα nuclear interacting partners in MCF7 breast cancer cell nuclei following estrogen and antiestrogen stimuli.
2020-09-02 | PXD018709 | Pride