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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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 5

CoREST complex inhibition in BRAFi-R melanoma cells induces global transcriptional upregulation and causes changes in cell-cycle, MAPK, and axon guidance signaling pathways.

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CoREST complex inhibition in BRAFi-R melanoma cells induces global trans...
(A) RNA-Seq profiling of 451Lu-R and 1205Lu-R melanoma cells following 24 hours of treatment with 5 μM PLX4032 versus 2.5 μM corin plus 5 μM PLX4032. Venn diagram illustrates corin plus PLX4032–induced upregulated and downregulated expression of cell line–specific and common genes compared with PLX4032 treatment alone (fold change [FC] ≥4, FDR <0.001). (B) K-means clustered (K = 6) heatmap of all genes showing significant expression changes (Padj < 0.01, |log2 FC| >2) upon corin treatment in at least 1 condition/cell line (i.e., with or without [w/o] PLX4032; 451Lu-R or 1205Lu-R). In each cell line, expression in the absence of PLX4032 and corin was set as reference (i.e., 0), and the relative expression changes were summarized as SD (σ). Numbers in the brackets indicate the gene counts in clusters. (C) GSEA of corin-induced common enriched pathways in 451Lu-R and 1205Lu-R melanoma cells. All gene sets displayed are significantly (P < 0.05) enriched with corin plus PLX4032 versus PLX4032 treatment alone. (D) GSEA of corin-induced distinct enriched pathways in 451Lu-R (top) and 1205Lu-R (bottom) melanoma cells. All gene sets displayed are significantly (P < 0.05) enriched with corin plus PLX4032 versus PLX4032 treatment alone. (E) GSEA in samples treated with corin plus PLX4032 versus those treated with PLX4032 alone illustrating representative common enriched gene sets in 451Lu-R (top) and 1205Lu-R (bottom) melanoma cells. NES, normalized enrichment score. n = 2 for all panels in this figure.