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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).

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