Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFβ1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p.
Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFβ1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p.
复制标题
DOI：
10.1158/1541-7786.mcr-16-0083
复制
发表时间：
2016-11
期刊：
影响因子：
--
通讯作者：
Govindarajan R
中科院分区：
文献类型：
--
作者：
Mody HR;Hung SW;AlSaggar M;Griffin J;Govindarajan R
鉴定用于联合化疗治疗人胰腺导管腺癌（PDAC）的表观遗传逆转剂仍然是一个未得到满足的临床需求。 Enhancer of Zeste Homolog 2 (EZH2) 的药理学抑制剂正在成为治疗各种实体瘤和白血病的潜在组蛋白甲基化逆转剂；然而，通过 EZH2 敲低鉴定出的令人惊讶的一小部分 mRNA 靶标表明，新的机制有助于其抗肿瘤作用。在这里，3-deazaneplanocin-A (DZNep) 是一种 S-腺苷-L-同型半胱氨酸水解酶和 EZH2 组蛋白赖氨酸-N-甲基转移酶的抑制剂，可显着重编程非编码 miRNA (miR) 表达并抑制胰腺癌中 TGFβ1 诱导的上皮间质 (EMT) 信号。特别是，miR-663a 和 miR-4787-5p 被鉴定为 PDAC 下调的 miR，被 DZNep 重新激活，直接靶向 TGFβ1 进行 RNA 干扰。慢病毒过表达 miR-663a 和 miR-4787-5p 会减少 PDAC 细胞中 TGFβ1 的合成和分泌，并部分模仿 DZNep 的 EMT 抵抗作用，而锁核酸 (LNA) antagomiR 则抵消了这些作用。 DZNep、miR-663a 和 miR-4787-5p 可减少原位小鼠胰腺肿瘤模型中的体内肿瘤负荷和转移。总而言之，这些发现表明，通过合成组蛋白甲基化逆转剂对 miR 进行表观遗传重编程是减弱 TGFβ1 诱导的人 PDAC 中 EMT 特征并揭示该过程中推定的 miR 靶点的可行方法。
Identification of epigenetic reversal agents for use in combination chemotherapies to treat human pancreatic ductal adenocarcinomas (PDAC) remains an unmet clinical need. Pharmacological inhibitors of Enhancer of Zeste Homolog 2 (EZH2) are emerging as potential histone methylation reversal agents for the treatment of various solid tumors and leukemia; however, the surprisingly small set of mRNA targets identified with EZH2 knockdown suggests novel mechanisms contribute to their anti-tumorigenic effects. Here, 3-deazaneplanocin-A (DZNep), an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone lysine-N-methyltransferase, significantly reprograms noncoding miRNA (miR) expression and dampens TGFβ1-induced epithelial-to-mesenchymal (EMT) signals in pancreatic cancer. In particular, miR-663a and miR-4787-5p were identified as PDAC-downregulated miRs that were reactivated by DZNep to directly target TGFβ1 for RNA interference. Lentiviral overexpression of miR-663a and miR-4787-5p reduced TGFβ1 synthesis and secretion in PDAC cells and partially phenocopied DZNep’s EMT-resisting effects, whereas locked nucleic acid (LNA) antagomiRs counteracted them. DZNep, miR-663a, and miR-4787-5p reduced tumor burden in vivo and metastases in an orthotopic mouse pancreatic tumor model. Taken together, these findings suggest the epigenetic reprogramming of miRs by synthetic histone methylation reversal agents as a viable approach to attenuate TGFβ1-induced EMT features in human PDAC and uncover putative miR targets involved in the process.