EZH2 Cooperates with DNA Methylation to Downregulate Key Tumor Suppressors and IFN Gene Signatures in Melanoma

EZH2 Cooperates with DNA Methylation to Downregulate Key Tumor Suppressors and IFN Gene Signatures in Melanoma.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1016/j.jid.2020.02.042
Journal or Publication Title: Journal of Investigative Dermatology
Volume: 140
Number: 12
Page Range: 2442-2454.e5
Date: 2020
Divisions: Melanoma Oncology and Immunology
Depositing User: General Admin
Identification Number: 10.1016/j.jid.2020.02.042
ISSN: 0022202X
Date Deposited: 05 Jan 2021 05:08

The histone methylase EZH2 is frequently dysregulated in melanoma and is associated with DNA methylation and silencing of genes involved in tumor suppression. In this study, we used chromatin immunoprecipitation and sequencing to identify key suppressor genes that are silenced by histone methylation in constitutively active EZH2(Y641) mutant melanoma and assessed whether these regions were also sites of DNA methylation. The genes identified were validated by their re-expression after treatment with EZH2 and DNA methyltransferase inhibitors. The expression of putative EZH2 target genes was shown to be highly relevant to the survival of patients with melanoma in clinical datasets. To determine correlates of response to EZH2 inhibitors, we screened a panel of 53 melanoma cell lines for drug sensitivity. We compared RNA sequencing profiles of sensitive to resistant melanoma cells and performed pathway analysis. Sensitivity was associated with strong downregulation of IFN-γ and IFN-α gene signatures that were reversed by treatment with EZH2 inhibitors. This is consistent with EZH2-driven dedifferentiated invasive states associated with treatment resistance and defects in antigen presentation. These results suggest that EZH2 inhibitors may be most effectively targeted to immunologically cold melanoma to both induce direct cytotoxicity and increase immune responses in the context of checkpoint inhibitor immunotherapy.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Tiffen, Jessamy
Gallagher, Stuart J.
Filipp, Fabian
Gunatilake, Dilini
Emran, Abdullah Al
Cullinane, Carleen
Dutton-Register, Ken
Aoude, Lauren
Hayward, Nick
Chatterjee, Aniruddha
Rodger, Euan J.
Eccles, Michael R.
Hersey, Peter
Last Modified: 05 Jan 2021 05:08
URI: https://eprints.centenary.org.au/id/eprint/913

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