G9A promotes tumor cell growth and invasion by silencing CASP1 in non-small-cell lung cancer cells.
G9A promotes tumor cell growth and invasion by silencing CASP1 in non-small-cell lung cancer cells.
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G9A通过沉默非小细胞肺癌细胞中的CASP1促进肿瘤细胞生长和侵袭
DOI：
10.1038/cddis.2017.65
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发表时间：
2017-04-06
影响因子：
9
通讯作者：
Zhang F
中科院分区：
文献类型：
--
作者：
Huang T;Zhang P;Li W;Zhao T;Zhang Z;Chen S;Yang Y;Feng Y;Li F;Shirley Liu X;Zhang L;Jiang G;Zhang F
非小细胞肺癌（NSCLC）是全球癌症相关死亡的主要原因之一。尽管已知表观遗传失调对于肿瘤进展很重要，但非小细胞肺癌的分子机制仍不清楚。在这里，我们发现 G9A（称为 EHMT2）是一种组蛋白甲基转移酶，负责组蛋白 3 (H3) 赖氨酸 9 (K9) 的单甲基化或二甲基化，在 NSCLC 中显着上调。敲低 G9A 或其活性的药物抑制可抑制肿瘤细胞的生长、集落形成、侵袭和迁移。此外，G9A 通过抑制 CASP1 表达来发挥这些功能。敲除 G9A 缺陷细胞中的 CASP1 可恢复肿瘤细胞侵袭和迁移的能力。从机制上讲，G9A 通过增加启动子周围的 H3K9me2 来沉默 CASP1 启动子活性。最后，G9A 的高表达或 CASP1 的低表达与肺腺癌的总体生存率较差相关。总的来说，我们的研究揭示了G9A通过沉默CASP1促进肿瘤细胞生长和侵袭的新机制，并暗示G9A可以作为治疗NSCLC的治疗靶点。
Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer-related death worldwide. Although epigenetic deregulation is known to be important for tumor progression, the molecular mechanisms in NSCLC remain unclear. Here, we found that G9A (known as EHMT2), a histone methyltransferase responsible for mono-or di-methylation of histone 3 (H3) lysine 9 (K9), is significantly upregulated in NSCLC. Knocking down G9A or pharmacological inhibition of its activity suppressed tumor cell growth, colony formation, invasion and migration. Furthermore, G9A exerts these functions by repressing CASP1 expression. Knocking down CASP1 in G9A-deficient cell restored capacities of tumor cell invasion and migration. Mechanistically, G9A silences the CASP1 promoter activity by increasing H3K9me2 around its promoter. Finally, high expression of G9A or low expression of CASP1 is correlated with poor overall survival in lung adenocarcinoma. Overall, our study uncovers a novel mechanism of G9A promoting tumor cell growth and invasion by silencing CASP1, and implies that G9A may serve as a therapeutic target in treating NSCLC.