Transcriptome analyses by RNA-seq with NELFE knockdown and EPZ-5676 or HMBA treated HCT116 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE234615 | GEO | 2023/07/01
REPOSITORIES: GEO
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Project description:To identify DOT1L targets, associated signaling pathways and networks in chondrocytes, we used genome-wide gene expression microarray analysis in human articular chondrocytes of 5 different donors (without known or documented joint disease) treated with EPZ-5676 or vehicle for 4 days. It is known that DOT1L inhibitors require longer time of treatment in order to show effect and influence the expression of MLL target genes in leukemia cells, but we opted for this relatively short inhibition time to be able to identify early changes induced by DOT1L inhibition. Human articular chondrocytes were obtained from 5 non-OA hip fracture patients. The cells were treated with 3 μM EPZ-5676 or vehicle (DMSO) for 4 days.
2017-04-20 | E-GEOD-77916 | biostudies-arrayexpress
Project description:To identify DOT1L targets, associated signaling pathways and networks in chondrocytes, we used genome-wide gene expression microarray analysis in human articular chondrocytes of 5 different donors (without known or documented joint disease) treated with EPZ-5676 or vehicle for 4 days. It is known that DOT1L inhibitors require longer time of treatment in order to show effect and influence the expression of MLL target genes in leukemia cells, but we opted for this relatively short inhibition time to be able to identify early changes induced by DOT1L inhibition.
2017-04-20 | GSE77916 | GEO
Project description:This study describes the transcriptome profiling of: 1) MM-401, a MLL1 specific inhibitor in MAF9 cells; 2) Comparation of the transcriptone profilings of MM-401,EPZ-5676 (Dot1L inhibitor), MI-2(Menin inhibitor) and iBET(Brd4 inhibitor) in MAF9 leukemia cells.
2016-05-12 | GSE68822 | GEO
Project description:Cells carrying MLL-rearrangements are sensitive to treatment with VTP-50469 with IC50 in 20-60 nM. We treated MOLM13 or RS4;11 cells with DMSO (0.33%) or VTP-50469 (100-330nM), followed by digital gene expression analyses of 3'end RNA-seq data. We found that very few genes significantly change expression >2-fold after 2 days of treatment, while after 7-day treatment more genes significantly changed expression >2-fold. The genes that lost expression after VTP-50469 treatment were enriched in MLL-fusion target genes and DOT1L-sensitive genes. Moreover, treatment with both EPZ-5676 and VTP-50469 suppress similar subsets of genes, however VTP-50469 suppress genes faster as compared to EPZ-5676. Treatment of PDX with VTP-50469 suppressed similar gene sets, namely MLL-fusion targets and DOT1L-sensitive genes.
2019-11-06 | GSE127506 | GEO
Project description:Gene expression array of human breast cancer cells MCF7 with DMSO-EPZ- EPZ+E2 and shDOT1L+E2 and ZR-75-1 after treatment with DMSO and EPZ
2019-02-08 | E-MTAB-6893 | biostudies-arrayexpress
Project description:Purpose: The chromosomal rearrangements of the mixed-lineage leukemia (MLL) gene have been extensively characterized as a potent oncogenic driver on the molecular and mechanistic level in acute lymphoblastic (ALL) and acute myeloid (AML) leukemia. For its oncogenic function the MLL fusion protein is hijacking the the multi enzyme super elongation complex (SEC) leading to elevated expression of MLL target genes (e.g. HOXA9 and MEIS). High expression of MLL target genes is overwriting the normal hematopoietic differentiation gene expression program, resulting in undifferentiated blasts cells having a more “stem-cell like” cancer-promoting phenotype. Although extensive resources have been devoted to a better understanding of therapeutic targets for the MLL fusion to overcome the de-differentiation, the inter-dependencies of those targets for the pathophysiology of MLL is still barely understood. Here we report a comparative mode of action analysis of different inhibitors potentially interfering with MLL fusion induced differentiation blockade. We used RNA-seq for transcriptomic profiling in 14 AML and ALL cell lines treated with DMSO control or one of the 5 studied inhibitors (EPZ-5676, Brequinar, BAY-155, BAY-1251152 and OTX015). Methods: We used RNA-seq for transcriptomic profiling in 14 AML and ALL cell lines treated with DMSO control or one of the 5 studied inhibitors (EPZ-5676, Brequinar, BAY-155, BAY-1251152 and OTX015). Results: We discovered significant differences between compounds in their ability to induce differentiation and interfere with MLL target genes expression. We observed that Menin and DOT1L inhibition act very specifically on MLL fused leukemia cell lines, whereas inhibition of BET, DHODH and P-TEFb have strong effects beyond the MLL fusion . Conclusions: These results show a substantial diversity in the molecular activities of those inhibitors and provide valuable insights into the further developmental potential as single agents or in combinations in MLL fused leukemias.
2019-06-24 | GSE125437 | GEO
Project description:DOT1L inhibition with EPZ-5676 in human articular chondrocytes from 5 non-OA hip fracture patients
| PRJNA312193 | ENA
Project description:Epigenetic regulation is a dynamic and reversible process that controls gene expression. Abnormal function results in downregulation or upregulation of pathways leading to diseases, such as cancer. The enzymes that establish and maintain epigenetic marks, such as histone methyltransferases (HMTs), are therapeutic targets as their and, importantly, the epigenetic modifications are reversible. Noteworthy, HMTs, as the other epigenetic enzymes and readers, form together multiprotein complexes that in concert regulate histone marks. To probe the epigenetic protein complexes in a biological system, we developed a reliable chemical biology high-content imaging strategy to screen compound libraries on multiple histone marks inside cells simultaneously. The advantage is double: (1) it identifies directly a drug that is active in cells on a specific histone mark and (2) it reveals the crosstalk between the epigenetic marks. By this approach, we identified that compound 4, a published CARM1 (PRMT4) inhibitor, inhibits both histone mark H3R2me2a (regulated by CARM1) and H3K79me2 (regulated by DOT1L) pointing out a synergistic interaction between the two HMTs. The results obtained by the screening assay were validated by mass spectrometry and other techniques confirming the crosstalk between the two marks and HMTs. Prompted by the interaction between CARM1 and DOT1L we combined compound 4 and DOT1L inhibitor EPZ-5676 resulting in a stronger cell proliferation inhibition and apoptosis, indicating that our approach provides also a novel strategy to identify effective synergistic drug combinations for cancer therapy.
2022-05-19 | PXD022873 | Pride
Project description:ChIP-Seq of ERalpha and DOT1L in MCF7 cell before and after EPZ and ICI treatment
2019-02-08 | E-MTAB-6883 | biostudies-arrayexpress
Project description:Estrogen Receptor alpha (ERα), a nuclear receptor with transcriptional activity, is a master regulator of estrogen signaling, widely known as therapeutic target in hormone-responsive breast cancer (BC). Moreover, ERα is highly expressed in approximately 80% of High Grade Serous Ovarian Cancer (HGSOC), the most common epithelial ovarian carcinoma. Despite some promising clinical trials evaluating endocrine therapy in this type of tumor, the role of ERα is still unknown. Epigenetic changes, such as DNA methylation, are emerging as key contributing factors to carcinogenesis. Disruptor of telomeric silencing-1-like (DOT1L), the only known histone methyl transferase capable to produce H3K79 mono, di and tri-methylation, modulates ERα actions in hormone-responsive BC. Considering this evidence, ERα-DOT1L association was confirmed in ERα-positive OC cells, PEO1 and PEO4, by Co-IP. DOT1L pharmacological inhibition by EPZ004777 (EPZ) revealed the involvement of this epigenetic enzyme in cell proliferation, cell cycle progression and apoptosis. Transcriptome profiling after ICI (a Selective Estrogen Receptor Degrader) and EPZ treatment, in both cell lines, has underlined a deep impact of both compounds on ERα-modulated genes, including the down-regulation of ERα itself. On the other hand, functional analysis showed that commonly affected transcripts are involved in different cellular processes, such as cancer cell survival, chemoresistance and cell cycle progression. Moreover, ChIP-qPCR performed on ERα promoter highlighted ERα and DOT1L co-localization, both in PEO1 and in PEO4 cells, which was reduced after EPZ treatment, suggesting a role of this complex on receptor transcriptional activity. In addition, drug combination studies performed with EPZ and ICI showed an additive effect in cell growth inhibition. Taken together, these results suggest DOT1L as a potential therapeutic target in the treatment of OC.
2019-11-04 | E-MTAB-8198 | biostudies-arrayexpress