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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DOI：
10.1016/j.jid.2020.02.042
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发表时间：
2020-12-01
影响因子：
6.5
通讯作者：
Hersey, Peter
中科院分区：
文献类型：
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作者：
Tiffen, Jessamy;Gallagher, Stuart J.;Hersey, Peter
组蛋白甲基化酶EZH 2在黑色素瘤中经常失调，并且与DNA甲基化和参与肿瘤抑制的基因沉默相关。在这项研究中，我们使用染色质免疫沉淀和测序，以确定关键的抑制基因，组蛋白甲基化沉默的组成型活性EZH 2（Y 641）突变黑色素瘤，并评估这些地区是否也是DNA甲基化的网站。通过用EZH 2和DNA甲基转移酶抑制剂处理后的重新表达来验证所鉴定的基因。在临床数据集中，推定的EZH 2靶基因的表达显示与黑素瘤患者的生存高度相关。为了确定对EZH 2抑制剂的反应的相关性，我们筛选了一组53个黑素瘤细胞系的药物敏感性。我们比较了敏感和耐药黑色素瘤细胞的RNA测序谱，并进行了通路分析。敏感性与IFN-γ和IFN-α基因特征的强烈下调相关，这些基因特征通过EZH 2抑制剂治疗逆转。这与EZH 2驱动的去分化侵袭状态一致，该状态与治疗抗性和抗原呈递缺陷相关。这些结果表明，EZH 2抑制剂可能最有效地靶向免疫冷黑色素瘤，以在检查点抑制剂免疫治疗的背景下诱导直接细胞毒性并增加免疫应答。
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-gamma and IFN-alpha 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.