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 6

Inhibition of the CoREST complex in BRAFi-R melanoma cells promotes transcriptional changes associated with the phenotype switch and increased expression of DUSP family MAPK inhibitors.

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Inhibition of the CoREST complex in BRAFi-R melanoma cells promotes tran...
(A) Heatmap of differential expression patterns of proliferative versus invasive gene signatures and transcriptional regulators associated with distinct melanoma phenotypes22 (indicated by a red asterisk) in 451Lu-R and 1205Lu-R melanoma cells treated with 2.5 μM corin or DMSO for 24 hours. (B) Comparison of the corin-associated intermediate phenotype gene expression signature in 451Lu-R and 1205Lu-R melanoma cells treated with 2.5 μM corin or DMSO for 24 hours and the published intermediate phenotype defined by Wouters et al. (26). (C) Volcano plots of differentially expressed genes (DEGs) (log2 FC >1, Padj < 0.01) in 451Lu-R (left) and 1205Lu-R (right) melanoma cells following 24 hours of treatment with 2.5 μM corin plus 5 μM PLX4032 versus 5 μM PLX4032 alone with highlighted changes in DUSP1, DUSP5, MITF, and AXL expression. (D) Heatmap of DUSP1/-4/-5/-6 expression in corin-treated BRAFi-S melanoma cells relative to DMSO treatment (2.5 μM, 24 hours). (E) Top known transcription factor–binding motifs enriched in corin-upregulated genes in 451Lu-R (left) and 1205Lu-R (right) melanoma cells.