TET1-Mediated Hypomethylation Activates Oncogenic Signaling in Triple-Negative Breast Cancer.
TET1-Mediated Hypomethylation Activates Oncogenic Signaling in Triple-Negative Breast Cancer.
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DOI：
10.1158/0008-5472.can-17-2082
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发表时间：
2018-08-01
期刊：
影响因子：
11.2
通讯作者：
Issa JJ
中科院分区：
文献类型：
--
作者：
Good CR;Panjarian S;Kelly AD;Madzo J;Patel B;Jelinek J;Issa JJ
DNA甲基化的获得和丧失在癌症中很常见，但控制这种甲基化平衡的因素仍不清楚。三阴性乳腺癌（TNBC）是一种不过度表达激素受体或HER 2/NEU的亚型，是观察到的最低甲基化的癌症之一。在这里，我们发现TET 1 DNA脱甲基酶在大约40%的TNBC患者中特异性过表达，它与高达10%的查询CpG位点的低甲基化和更差的总生存期相关。通过对乳腺癌和卵巢癌细胞系的生物信息学分析，我们发现了一个复杂的网络，将TET 1与低甲基化和癌症特异性致癌途径（包括PI 3 K，EGFR和PDGF）的激活联系起来。TET 1表达与对靶向PI 3 K-mTOR通路的药物的敏感性相关，并且在两个独立的TNBC细胞系中CRISPR介导的TET 1缺失导致PI 3 K通路基因的表达降低、免疫应答基因的上调和细胞增殖的大幅降低，表明致癌通路对TET 1过表达的依赖性。我们的工作确立了TET 1作为一种潜在的致癌基因，有助于癌症中的异常低甲基化，并表明TET 1可以作为治疗干预的药物靶点。
Both gains and losses of DNA methylation are common in cancer, but the factors controlling this balance of methylation remain unclear. Triple-negative breast cancer (TNBC), a subtype that does not overexpress hormone receptors or HER2/NEU, is one of the most hypomethylated cancers observed. Here we discovered that the TET1 DNA demethylase is specifically overexpressed in about 40% of patients with TNBC, where it is associated with hypomethylation of up to 10% of queried CpG sites and a worse overall survival. Through bioinformatic analyses in both breast and ovarian cancer cell line panels, we uncovered an intricate network connecting TET1 to hypomethylation and activation of cancer-specific oncogenic pathways including PI3K, EGFR, and PDGF. TET1 expression correlated with sensitivity to drugs targeting the PI3K-mTOR pathway, and CRISPR-mediated deletion of TET1 in two independent TNBC cell lines resulted in reduced expression of PI3K pathway genes, upregulation of immune response genes, and substantially reduced cellular proliferation, suggesting dependence of oncogenic pathways on TET1 overexpression. Our work establishes TET1 as a potential oncogene that contributes to aberrant hypomethylation in cancer and suggests that TET1 could serve as a druggable target for therapeutic intervention.