Fiche publication
Date publication
janvier 2025
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr COIN Frédéric
,
Dr DAVIDSON Irwin
,
Dr EGLY Jean-Marc
,
Dr COMPE Emmanuel
Tous les auteurs :
Cigrang M, Obid J, Nogaret M, Seno L, Ye T, Davidson G, Catez P, Berico P, Capelli C, Marechal C, Zachayus A, Elly C, Guillen Navarro MJ, Martinez Diez M, Santamaria Nunez G, Li TK, Compe E, Avilés P, Davidson I, Egly JM, Cuevas C, Coin F
Lien Pubmed
Résumé
The plasticity of cancer cells facilitates their ability to adopt heterogeneous differentiation states, posing a significant challenge to therapeutic interventions. Specific gene expression programs, driven in part by super-enhancers (SEs), underlie cancer cell states. Here we successfully inhibit SE-driven transcription in phenotypically distinct metastatic melanoma cells using next-generation synthetic ecteinascidins. Through functional genomic methodologies, we demonstrate that these compounds inhibit the expression of genes encoding lineage-specific or ubiquitous transcription factors/coactivators by selectively targeting the CpG-rich sequences within their promoters and/or enhancers. This prevents the formation of transcription factor/coactivator condensates necessary for SE-dependent gene expression. Consequently, these compounds exhibit cytotoxic activity across distinct subpopulations of metastatic melanoma cells and inhibit tumor proliferation, including those resistant to current therapies. These findings extend to other cancers, like small cell lung cancer, recently approved for ecteinascidin-based treatment. Overall, our study provides preclinical proof that pan-inhibition of SE-dependent genes with synthetic ecteinascidins is a promising therapeutic approach for tumors with heterogeneous transcriptional landscapes.
Mots clés
Humans, Cell Line, Tumor, Enhancer Elements, Genetic, genetics, Gene Expression Regulation, Neoplastic, drug effects, Antineoplastic Agents, pharmacology, Animals, Melanoma, drug therapy, Transcription, Genetic, drug effects, Mice, Cell Proliferation, drug effects, Transcription Factors, metabolism, Promoter Regions, Genetic, genetics, Xenograft Model Antitumor Assays
Référence
Nat Commun. 2025 01 8;16(1):512
