The CoREST repressor complex mediates phenotype switching and therapy resistance in melanoma
Muzhou Wu, … , Philip A. Cole, Rhoda M. Alani
Muzhou Wu, … , Philip A. Cole, Rhoda M. Alani
Published February 1, 2024
Citation Information: J Clin Invest. 2024;134(6):e171063. https://doi.org/10.1172/JCI171063.
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Research Article Dermatology Oncology

The CoREST repressor complex mediates phenotype switching and therapy resistance in melanoma

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.

Authors

Muzhou Wu, Ailish Hanly, Frederick Gibson, Robert Fisher, Samantha Rogers, Kihyun Park, Angelina Zuger, Kevin Kuang, Jay H. Kalin, Sarah Nocco, Matthew Cole, Amy Xiao, Filisia Agus, Adam Labadorf, Samuel Beck, Marianne Collard, Philip A. Cole, Rhoda M. Alani

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Figure 9

CoREST complex inhibition promotes a response to BRAFi therapy in BRAFi-R melanoma through DUSP1 upregulation.

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CoREST complex inhibition promotes a response to BRAFi therapy in BRAFi-...
(A) Western blot analysis of 1205Lu-R and 451Lu-R melanoma cells treated with DMSO, 5 μM PLX4032 alone, 2.5 μM corin alone, or 2.5 μM corin plus 5 μM PLX4032 for 24 hours. Western blots were run contemporaneously with the exception of DUSP1. DUSP1 expression in 1205Lu-R and 451Lu-R cells was evaluated on separate Western blots, as denoted by the separating dotted line. Quantification of the relative expression of p-p38 (active) versus p38 (total) protein expression relative to the DMSO control is shown below each p-p38 band. (B and C) Quantification of DUSP1, -4, -5, and -6 mRNA expression levels (RT-qPCR) in BRAFi-S (S) versus BRAFi-R (R) 451Lu (B) and 1205Lu (C) melanoma cells (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001, by 2-tailed, unpaired t test. (D) DUSP1 expression levels (RT-qPCR) in 451Lu-R, 1205Lu-R, SkMel28-R, and A375-R melanoma cells treated with DMSO or 2.5 μM corin for 2, 4, 8, or 24 hours. *P < 0.05 and ***P < 0.001, by 1-way ANOVA with Tukey’s test. (E) Proliferation of 1205Lu-R melanoma cells overexpressing DUSP1 versus control (Ctrl) vector, treated with increasing doses of PLX4032 for 72 hours. *P < 0.05 and **P < 0.01, by 2-way ANOVA with Tukey’s test. The morphology of 1205Lu-R melanoma cells following vector control (top) or DUSP1 overexpression (bottom) is depicted on the right. Representative images shown. Scale bar: 100 μm. (F) Quantification of DUSP1 expression in normal skin (n = 7), benign nevi (n = 18), and malignant melanoma (n = 44) tissues from patients. Data were generated using microarray data from Talantov et al. (61). ***P < 0.001 and ****P < 0.0001, by 1-way ANOVA with Tukey’s test. (G) Kaplan-Meier curves illustrating the correlation of DUSP1/RCOR1 expression in patients’ tumor specimens (split at the median) and overall survival using data obtained from TCGA melanoma database (https://portal.gdc.cancer.gov).