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Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by targeting super-enhancer-driven oncogenic transcription [Cut & Tag, ATAC-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE256094 | GEO | 2024/02/23

REPOSITORIES: GEO

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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.

2024-02-23 | GSE256100 | GEO

MY-COMP, an inhibitor of the transcriptional activity of YAP-B-MYB, identifies NEK2 as a novel mediator of YAP oncogenesis in uveal melanoma cells [RNA-seq]

Project description:Activation of YAP is frequently observed in cancer and is associated with poor outcomes, making it an attractive target for therapeutic intervention. Previous studies have mainly focused on blocking the interaction of YAP with TEAD transcription factors. Here we took a different approach by interfering with the binding of YAP to the transcription factor B-MYB using MY-COMP, a fragment of B-MYB containing the YAP binding domain fused to a nuclear localization signal. We found that expression of MY-COMP inhibited the binding of B-MYB to YAP, resulting in growth defects, nuclear abnormalities and polyploidization in HeLa cells. Additionally, MY-COMP interfered with normal cell cycle progression of YAP-dependent uveal melanoma cells, but its effects were much weaker in YAP-independent cutaneous melanoma cell lines. MY-COMP antagonized the YAP-dependent expression of MMB-regulated cell cycle genes, providing an explanation for the observed phenotypes. We identified NIMA-related kinase (NEK2) as a candidate target downstream of YAP and B-MYB, contributing to the transformation of YAP-dependent uveal tumor cell lines. Overall, our findings suggest that targeting selected YAP-MMB regulated genes such as NEK2 or inhibiting the WW-domains of YAP to suppress YAP-regulated cell cycle genes could provide a novel mechanism to antagonize the pro-tumorigenic functions of YAP.

2024-03-06 | GSE227973 | GEO

MY-COMP, an inhibitor of the transcriptional activity of YAP-B-MYB, identifies NEK2 as a novel mediator of YAP oncogenesis in uveal melanoma cells [CUT&RUN]

2024-03-06 | GSE227972 | GEO

PM01183 on SCLC cell lines [ChIP-Seq, DMS-53]