Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Biochim Biophys Acta Mol Basis Dis. 2018 Sep;1864(9 Pt B):2835-2844. doi: 10.1016/j.bbadis.2018.05.015. Epub 2018 May 23.
IRX1 is originally characterized as a tumor suppressor gene of gastric cancer (GC) by our group based on serially original studies. However, the molecular regulatory mechanisms of IRX1 are not clear yet. Here, we identified protein arginine methyltransferase 5 (PRMT5) as a major upstream regulator of IRX1 for determining GC progression. Expression of PRMT5 was significantly increased in human GC tissues (433 out of 602 cases, 71.93%) compared with normal gastric mucosa, and exhibited diagnostic and prognostic potential. Overexpression of PRMT5 promoted tumorigenicity and metastasis of GC cells, while knockdown of PRMT5 abrogated tumorigenicity and metastasis of GC cells in vitro and in vivo. By co-immunoprecipitation and chromatin immunoprecipitation assays, we proved that PRMT5 elevated methylation levels of tumor suppressor IRX1 promoter via recruiting DNMT3A at promoter region. Knockdown of PRMT5 in SGC7901 and NCI-N87 cells decreased the recruitment of DNMT3A at IRX1 promoter, and reduced the methylation level of IRX1 promoter, then re-activated IRX1 expression. Whereas, overexpression of PRMT5 could epigenetically suppress IRX1 expression. Overall, PRMT5 promoted tumorigenicity and metastasis of gastric cancer cells via epigenetic silencing of IRX1. Targeting PRMT5 in GC might inhibit the malignant characters of GC and drawing a novel therapeutic potential.
IRX1 最初被我们团队鉴定为胃癌（GC）的肿瘤抑制基因，这是基于一系列原始研究。然而，IRX1 的分子调控机制尚不清楚。在这里，我们确定蛋白精氨酸甲基转移酶 5（PRMT5）是决定 GC 进展的 IRX1 的主要上游调节剂。与正常胃黏膜相比，PRMT5 在人类 GC 组织中的表达显著增加（602 例中有 433 例，71.93%），具有诊断和预后潜力。PRMT5 的过表达促进了 GC 细胞的致瘤性和转移，而 PRMT5 的敲低则在体外和体内消除了 GC 细胞的致瘤性和转移。通过共免疫沉淀和染色质免疫沉淀实验，我们证明 PRMT5 通过在启动子区域募集 DNMT3A 来提高肿瘤抑制基因 IRX1 启动子的甲基化水平。在 SGC7901 和 NCI-N87 细胞中敲低 PRMT5 降低了 IRX1 启动子处 DNMT3A 的募集，并降低了 IRX1 启动子的甲基化水平，从而重新激活了 IRX1 的表达。而 PRMT5 的过表达则可以通过表观遗传抑制 IRX1 的表达。总的来说，PRMT5 通过对 IRX1 的表观遗传沉默促进了胃癌细胞的致瘤性和转移。在 GC 中靶向 PRMT5 可能抑制 GC 的恶性特征，并为治疗提供新的潜力。
