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The CoREST repressor complex mediates phenotype switching and therapy resistance in melanoma
- Source :
- Journal of Clinical Investigation. March 15, 2024, Vol. 134 Issue 6
- Publication Year :
- 2024
-
Abstract
- Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated. Here, we evaluated the corepressor for element 1-silencing transcription factor (CoREST) epigenetic repressor complex and the recently developed bivalent inhibitor corin within the context of melanoma phenotype plasticity and therapeutic resistance. We found that CoREST was a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells led to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin revealed specific effects on histone marks connected to epithelial-mesenchymal transition-associated (EMT-associated) transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor-resistant (BRAFi-R) melanomas with corin promoted resensitization to BRAFi therapy. DUSP1 was consistently downregulated in BRAFi-R melanomas, which was reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity was recapitulated by the p38 MAPK inhibitor BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial for patients with BRAFi-resistant melanoma.<br />Introduction Melanomas exhibit tremendous intratumoral heterogeneity and phenotype plasticity, which allows them to switch between distinctive transcriptional programs in response to external stressors, including targeted therapies (1). These transcriptional phenotypes, [...]
- Subjects :
- Thermo Fisher Scientific Inc.
Scientific equipment and supplies industry -- Health aspects -- Genetic aspects
Chromatin -- Health aspects -- Genetic aspects
Stem cells -- Genetic aspects -- Health aspects
Vemurafenib -- Health aspects
Phosphatases -- Genetic aspects -- Health aspects
Cancer -- Care and treatment
Epigenetic inheritance -- Genetic aspects -- Health aspects
Melanoma -- Genetic aspects
DNA binding proteins -- Genetic aspects -- Health aspects
Health care industry
Boston University. Medical Center Hospital
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 134
- Issue :
- 6
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.790361055
- Full Text :
- https://doi.org/10.1172/JCI171063.