2. Academic Validation
  3. 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

  • J Invest Dermatol. 2020 Dec;140(12):2442-2454.e5. doi: 10.1016/j.jid.2020.02.042.
Jessamy Tiffen 1,  Stuart J Gallagher 1,  Fabian Filipp 2,  Dilini Gunatilake 1,  Abdullah Al Emran 1,  Carleen Cullinane 3,  Ken Dutton-Register 4,  Lauren Aoude 5,  Nick Hayward 4,  Aniruddha Chatterjee 6,  Euan J Rodger 6,  Michael R Eccles 6,  Peter Hersey 7
Affiliations

Affiliations

  • 1 Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
  • 2 Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, Merced, California, USA.
  • 3 Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 4 QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
  • 5 The University of Queensland Diamantina Institute, Brisbane, Queensland, Australia.
  • 6 Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand.
  • 7 Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Electronic address: [email protected].
PMID: 32360600 DOI: 10.1016/j.jid.2020.02.042
Abstract

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.

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