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Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by targeting super-enhancer-driven oncogenic transcription

ABSTRACT: Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by targeting super-enhancer-driven oncogenic transcription

PROVIDER: PRJNA1078234 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28013800.fastq.gz	Fastqsanger.gz
	SRR28013801.fastq.gz	Fastqsanger.gz
	SRR28013802.fastq.gz	Fastqsanger.gz
	SRR28013803.fastq.gz	Fastqsanger.gz
	SRR28013804.fastq.gz	Fastqsanger.gz

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Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by targeting super-enhancer-driven oncogenic transcription [RNA-Seq]

Project description:Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by targeting super-enhancer-driven oncogenic transcription [RNA-Seq]

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Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by targeting super-enhancer-driven oncogenic transcription [RNA-Seq]

Project description:Melanoma cells exhibit a dynamic capacity for transitioning through various cellular states. This intricate biological trait poses significant challenges to current therapeutics approaches, emphasizing the urgent need for innovative treatment strategies. Here, we initially demonstrated the efficacy of Lurbinectedin, a synthetic ecteinascidin derived from marine sources, against melanoma cells, irrespective of their driver mutations or phenotypic manifestations. Subsequently, we designed and evaluated two derivatives of Lurbinectedin, termed Ecubectedin and PM54(Comp IA), both of which fully recapitulate the cytotoxic effects of Lurbinectedin in vitro and might present benefits versus the original compound. These derivatives also exert a noteworthy in vivo impact on tumor growth and animal survival, inducing apoptosis in melanoma cells. Mechanistically, our investigations revealed that ecteinascidins strongly inhibit oncogenic super-enhancer-mediated gene expression by a three-pronged mechanism. Firstly, the binding to the promoters of lineage-specific master transcription factors and the disruption of their associated auto-regulatory circuits, secondly, the binding and inhibition of genes encoding ubiquitous transcription factors/coactivators, heavily enriched at oncogenic SEs, and thirdly, the direct drug-binding to these regulatory elements, seemingly hampering the assembly of transcriptional condensates, all likely work in tandem to disrupt oncogene expression. These findings underscore the potential of ecteinascidins as promising therapeutics for melanoma and potentially other transcriptionally-addicted cancers.

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Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by targeting super-enhancer-driven oncogenic transcription

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Project description:Super-enhancers and stretch enhancers (SEs) drive expression of genes that play prominent roles in normal and disease cells, but the functional importance of these clustered enhancer elements is poorly understood, so it is not clear why genes key to cell identity have evolved regulation by such elements. Here we show that super-enhancers consist of functional constituent units that concentrate multiple developmental signaling pathways at key pluripotency genes in embryonic stem cells and confer responsiveness to signaling of their associated genes. Cancer cells frequently acquire SEs at genes that promote tumorigenesis, and we show that these genes are especially sensitive to perturbation of oncogenic signaling pathways. Super-enhancers thus provide a platform for signaling pathways to regulate genes that control cell identity during development and tumorigenesis. ChIP-Seq for H3K27ac and RNA Pol II in mouse embryonic stem cells with CRISPR-deleted enhancers

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