Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA; Center for Genomic and Computational Biology, Duke University, Durham, NC 27710, USA.
Cell Rep. 2020 Nov 3;33(5):108341. doi: 10.1016/j.celrep.2020.108341.
Dysregulated gene expression is a common feature of cancer and may underlie some aspects of tumor progression, including tumor relapse. Here, we show that recurrent mammary tumors exhibit global changes in gene expression and histone modifications and acquire dependence on the G9a histone methyltransferase. Genetic ablation of G9a delays tumor recurrence, and pharmacologic inhibition of G9a slows the growth of recurrent tumors. Mechanistically, G9a activity is required to silence pro-inflammatory cytokines, including tumor necrosis factor (TNF), through H3K9 methylation at gene promoters. G9a inhibition induces re-expression of these cytokines, leading to p53 activation and necroptosis. Recurrent tumors upregulate receptor interacting protein kinase-3 (RIPK3) expression and are dependent upon RIPK3 activity. High RIPK3 expression renders recurrent tumors sensitive to necroptosis following G9a inhibition. These findings demonstrate that G9a-mediated silencing of pro-necroptotic proteins is a critical step in tumor recurrence and suggest that G9a is a targetable dependency in recurrent breast cancer.
基因表达失调是癌症的一个常见特征，可能是肿瘤进展某些方面的基础，包括肿瘤复发。在这里，我们表明复发性乳腺肿瘤表现出基因表达和组蛋白修饰的全局变化，并获得了对 G9a 组蛋白甲基转移酶的依赖性。G9a 的遗传缺失延迟了肿瘤复发，而 G9a 的药物抑制减缓了复发性肿瘤的生长。在机制上，G9a 通过组蛋白 H3K9 甲基化在基因启动子上沉默促炎细胞因子（包括肿瘤坏死因子（TNF）），需要 G9a 活性。G9a 抑制诱导这些细胞因子的重新表达，导致 p53 激活和坏死性凋亡。复发性肿瘤上调受体相互作用蛋白激酶-3（RIPK3）的表达，并依赖于 RIPK3 的活性。高 RIPK3 表达使复发性肿瘤在 G9a 抑制后对坏死性凋亡敏感。这些发现表明，G9a 介导的促坏死性凋亡蛋白沉默是肿瘤复发的关键步骤，并表明 G9a 是复发性乳腺癌的一个可靶向依赖性。
