H3K9 dimethylation safeguards cancer cells against activation of the Interferon pathway [ChIP-seq]. H3K9 dimethylation safeguards cancer cells against activation of the Interferon pathway [ChIP-seq]

Activation of the interferon genes constitutes an important anticancer pathway, able to restrict proliferation of cancer cells. Here we demonstrate that the H3K9me3 histone methyl transferase (HMT) Suppressor Of Variegation 3-9 Homolog 1 (SUV39H1) is required for the proliferation of Acute Myeloid Leukemia (AML) and find that its loss leads to activation of the interferon pathway. Mechanistically, we show that this occur via destabilization of a complex composed of SUV39H1 and the two H3K9me2 HMTs G9a and GLP. Indeed, loss of H3K9me2 correlated with the activation of key interferon pathway genes and interference with the activities of G9a/GLP largely phenocopied loss of SUV39H1. Finally, we demonstrated that inhibition of G9a/GLP synergized with DNA demethylating agents and that SUV39H1 constitutes a potential biomarker the response to hypomethylation treatment. Collectively, we uncovered a clinical relevant role for H3K9me2 in safeguarding cancer cells against activation of the interferon pathway. Overall design: Examination of H3K9me2 and H3K9me3 histone modifications after disruption of the SUV39H1/G9a/GLP protein complex

干扰素基因的激活是一条重要的抗肿瘤通路，能够限制癌细胞的增殖。本研究证实，H3K9me3组蛋白甲基转移酶（histone methyl transferase, HMT）异染色质蛋白1抑制因子同源物1（Suppressor Of Variegation 3-9 Homolog 1, SUV39H1）是急性髓系白血病（Acute Myeloid Leukemia, AML）细胞增殖所必需的，且其缺失会导致干扰素通路的激活。
从机制层面分析，该现象通过破坏SUV39H1与两种H3K9me2组蛋白甲基转移酶G9a、GLP组成的复合物稳定性而发生。研究发现，H3K9me2水平的降低与关键干扰素通路基因的激活呈显著相关，而干扰G9a/GLP的活性在很大程度上模拟了SUV39H1缺失的表型。
最后，本研究证实，抑制G9a/GLP可与DNA去甲基化试剂产生协同作用，且SUV39H1可作为响应低甲基化治疗的潜在生物标志物。综上，本研究揭示了H3K9me2在保护癌细胞免于激活干扰素通路方面具有临床相关的作用。
整体实验设计：在破坏SUV39H1/G9a/GLP蛋白质复合物后，检测H3K9me2与H3K9me3的组蛋白修饰水平