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Transcriptome analysis of wild-type and drug-resistance-induced melanoma cell lines

ABSTRACT: Transcriptional co-acticvators inhibition is proving to be a powerful mean against cancer cells that shown a novel hallmarks named transcriptional addiction. This dependecy on co-activars activity lays on their presence in clusters of enhancer regulatory regions called Super-enhancers (SEs) that establish high level of expression of genes important for cancer phisiology such as oncogenes and master transcription factors of the cellular lineage of origin. Among these co-activators in SEs is the kinase CDK7 of the basal transcription factor TFIIH. Here, using a large panel of melanoma cell lines, we observed an overall dependency of melanoma cells in CDK7 activity by inhibiting its function through the drug THZ1. However, by chronically exposing melanoma cells to THZ1, they univocally become resistant, switching phenotype toward a mesenchymal-like state.

ORGANISM(S): Homo sapiens

PROVIDER: GSE158119 | GEO | 2020/09/18

REPOSITORIES: GEO

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GATA6 gene regulatory network drives multi drug resistance in cutaneous melanoma

Project description:Transcriptional co-acticvators inhibition is proving to be a powerful mean against cancer cells that shown a novel hallmarks named transcriptional addiction. This dependecy on co-activars activity lays on their presence in clusters of enhancer regulatory regions called Super-enhancers (SEs) that establish high level of expression of genes important for cancer phisiology such as oncogenes and master transcription factors of the cellular lineage of origin. Among these co-activators in SEs is the kinase CDK7 of the basal transcription factor TFIIH. Here, using a large panel of melanoma cell lines, we observed an overall dependency of melanoma cells in CDK7 activity by inhibiting its function through the drug THZ1. However, by chronically exposing melanoma cells to THZ1, they univocally become resistant, switching phenotype toward a mesenchymal-like state. By comparing the transcriptome of artificial resistant and untreated cells in culture, we observed upregulation of the transcription factor GATA6 which control indeed a small regulon that includes genes involved in multi-drug resistance (MDR).

2021-01-09 | GSE164431 | GEO

Genome-wide distribution of CDK7 in human cutaneous melanoma

Project description:CDK7 is a cycline-dependent kinase part of the basal transcription factor TFIIH involved in the formation of the pre-inithiation complex of RNApol II dependent-genes. Despite it's well known genomic localization at the level of gene's promoter, it has been recently observed from Kwiatkowski et al., (2014) that CDK7 can be found also in large clusters of gene regulatory elements called Super-enhancers (SEs) of both normal and cancer cells. Here we report that CDK7 is resembling such distribution in a human melanoma context, in particular at the level of genes important in melanoma physiology such as the master transcription factors MITF and SOX10 which indeed, following the inhibition of CDK7 with the molecule THZ1, are rapidly downregulated at very low nanomolar concentration.

2020-09-18 | GSE158118 | GEO

Gene expression profiles of BxPC-3, MiaPaCa-2 and PANC-1 cell lines treated with DMSO and THZ1 respectively

Project description:By screening an epigenetic-related compound library, we identified THZ1, a covalent inhibitor of CDK7, as a promising candidate. Multiple long-established and patient-derived PDAC cell lines (PDC) were used to validate the efficacy of THZ1 in vitro. In addition, patient-derived xenograft (PDX) models and animal models of PDAC were utilized for examining THZ1 efficacy in vivo. Furthermore, RNA-Seq and H3K27Ac-based Super-Enhancers (SEs) analyses were performed to reveal the molecular mechanism of THZ1 treatment. Lastly, PDAC cell lines with primary or acquired resistance to THZ1 were investigated to explore the potential mechanism of THZ1 susceptibility.

2019-02-01 | GSE121273 | GEO

CDK7 Inhibition Suppresses Melanoma Growth By Depleting A Super-enhancer Associated "Achilles" Lineage Cluster [ChIP-Seq]

Project description:Cutaneous malignant melanoma (CMM) lacks targeted therapies beyond the oft-circumvented BRAF inhibitors. Part of the difficulty in treating melanomas has been attributed to a strong survival program controlled by melanocyte transcription factors such as MITF - a phenomenon first described in melanoma as “lineage dependency.” Recently, a highly selective covalent CDK7 inhibitor (THZ1) has been shown to potently suppress the growth of various cancers through the depletion of master transcription-regulating oncogenes and the disruption of their attendant super-enhancers. We now show that melanoma cells are highly sensitive to CDK7 inhibition and that a melanocyte “lineage cluster,” whose members are transcriptionally driven by super-enhancers, is also strongly suppressed by THZ1. These results point to CDK7 inhibition as a viable strategy to deprive oncogenic transcription and suppress tumor growth in melanoma.

2017-10-23 | GSE75814 | GEO

CDK7 Inhibition Suppresses Melanoma Growth By Depleting A Super-enhancer Associated Achilles Lineage Cluster [Array]

2017-10-23 | GSE75810 | GEO

Effect of CDK7 inhibitor on MYCN-amplified retinoblastoma

Project description:Retinoblastoma (RB) is a common malignancy that primarily affects pediatric populations. Although a well-known cause of RB is RB1 mutation, MYCN amplification can also lead to the disease, which is a poor prognosis factor. Studies conducted in various tumor types have shown that MYCN inhibition is an effective approach to impede tumor growth. Various indirect approaches have been developed to overcome the difficulty of directly targeting MYCN, such as modulating the super enhancer (SE) upstream of MYCN. The drug used in this study to treat MYCN-amplified RB was THZ1, a CDK7 inhibitor that can effectively suppress transcription by interfering with the activity of SEs. The study findings confirmed the anticancer activity of THZ1 against RB in both in vitro and in vivo experiments. Therapy with THZ1 was found to affect numerous genes in RB according to the RNA-seq analysis. Moreover, the gene expression changes induced by THZ1 treatment were enriched in ribosome, endocytosis, cell cycle, apoptosis, etc. Furthermore, the combined analysis of ChIP-Seq and RNA-seq data suggested a potential role of SEs in regulating the expression of critical transcription factors, such as MYCN, OTX2, and SOX4. Moreover, ChIP‒qPCR experiments were conducted to confirm the interaction between MYCN and SEs. In conclusion, THZ1 caused substantial changes in gene transcription in RB, resulting in inhibited cell proliferation, interference with the cell cycle, and increased apoptosis. The efficacy of THZ1 is positively correlated with the degree of MYCN amplification and is likely exerted by interfering with MYCN upstream SEs.

2023-07-04 | GSE236205 | GEO

Genome-wide maps of chromatin state in primary MLL-AF9 AML

Project description:Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly-gained SEs in primary mouse AML cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes. We show that blocking CKIα together CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis.

2018-08-23 | GSE117443 | GEO

CDK7 inhibition suppresses Castration-Resistant Prostate Cancer through MED1 inactivation

Project description:We performed RNA-seq and ChIP-seq in three prostate cell lines (VCaP, LNCaP and DU145) to ascertain the role of the mediator complex MED1 in AR signaling. Upon androgen stimulation, MED1 undergoes phosphorylation by CDK7 and physically engages with AR at super-enhancer sites, which is essential for AR-mediated transcription. The CDK7 specific inhibitor THZ1 blunts AR-dependent neoplastic growth by preventing the co-recruitment of AR/MED1 in a genome-wide fashion, and reverts the enzalutamide resistance characterized by hyper-phosphorylated MED1. The effect of THZ1 phenocopies that for MED1 and CDK7 knockdown.

2019-08-20 | GSE125245 | GEO

Targeting of Super-Enhancer-Associated Oncogenic Transcription in MYCN-driven tumor cells by CDK7 inhibition [Gene Expression]

Project description:Global gene expression after CDK7 inhibition by THZ1 Global gene expression after genetic knockdown or overexpression of MYCN

2014-11-21 | E-GEOD-62724 | biostudies-arrayexpress

Differential gene expression analysis of MYCN-amplified neuroblastoma cells after THZ1 and TKI combination therapy.

Project description:The CDK7 inhibitor THZ1 has been shown to suppress MYCN gene transcription but not cause significant cell death as a single agent. The tyrosine kinase inhibitors (TKIs) ponatinib and lapatinib were found to exert synergistic anti-cancer effects in combination with the CDK7 inhibitor THZ1, on MYCN amplified neuroblastoma cell lines.

2020-03-20 | GSE128649 | GEO

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