Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, China.
Department of Chinese Medicine, Shandong Provincial Western Hospital, China.
Biomed Pharmacother. 2019 Jul;115:108924. doi: 10.1016/j.biopha.2019.108924. Epub 2019 May 14.
KMT2D, a kind of histone H3 lysine 4 (H3K4) methyltransferase, its abnormal expression confirmed to be associated with diverse tumors, but is lack of defined role in bladder cancer (BC). KMT2D mutation was analyzed using several databases. Immunohistochemistry and clinicopathological analysis of KMT2D in 51 paired of BC tissues and corresponding normal tissues were used to evaluate the relationship between KMT2D and BC. The effects of silencing or over-expressing KMT2D on HTB-9 and T24 cell viability, migration and invasion were performed using MTT, wound scratch and Transwell, respectively. Also, bladder cancer mouse model was established by hypodermic injection of the BC cells. Associated expressions of methylation genes, oncogenes and tumor suppressors were assessed by western blot and quantitative real-time PCR. KMT2D was frequent mutation in various tumors, including BC. It was negative expression in BC tissues and cells, also implicated with tumor stages and lymph node metastasis. In silencing KMT2D HTB-9 and T24 cells, cell viability, migration and invasion were notably promoted. Meanwhile, knockdown of KMT2D benefited to solid tumor formation in vivo. However, over-expressing KMT2D represented contrary results. Especially, KMT2D over-expression induced the activity of H3K4 monomethylation (me1), and effectively enhanced PTEN and p53 expressions as well as repressed STAG2 expression. Meanwhile, KMT2D had no obvious effect on Survivin. This work suggested an anti-tumor role for KMT2D in vitro and in vivo, as well as provided a possible tumor inhibition mechanism in which KMT2D enhanced H3K4me1 activity to support the expressions of tumor suppressors.
KMT2D 是一种组蛋白 H3 赖氨酸 4（H3K4）甲基转移酶，其异常表达被证实与多种肿瘤有关，但在膀胱癌（BC）中缺乏明确的作用。使用多个数据库分析 KMT2D 突变。通过免疫组织化学和 51 对 BC 组织及其相应正常组织中 KMT2D 的临床病理分析，评估 KMT2D 与 BC 的关系。分别通过 MTT、划痕实验和 Transwell 检测沉默或过表达 KMT2D 对 HTB-9 和 T24 细胞活力、迁移和侵袭的影响。此外，通过皮下注射 BC 细胞建立膀胱癌小鼠模型。通过 Western blot 和定量实时 PCR 评估甲基化基因、癌基因和肿瘤抑制基因的相关表达。KMT2D 在包括 BC 在内的各种肿瘤中频繁发生突变。它在 BC 组织和细胞中呈阴性表达，也与肿瘤分期和淋巴结转移有关。沉默 KMT2D 后 HTB-9 和 T24 细胞的活力、迁移和侵袭明显增强。同时，KMT2D 的敲低有利于体内实体瘤的形成。然而，过表达 KMT2D 则代表相反的结果。特别是，KMT2D 过表达诱导 H3K4 单甲基化（me1）的活性，并有效增强了 PTEN 和 p53 的表达，同时抑制了 STAG2 的表达。同时，KMT2D 对 Survivin 没有明显影响。这项工作表明 KMT2D 在体外和体内具有抗肿瘤作用，并提供了一种可能的肿瘤抑制机制，即 KMT2D 增强 H3K4me1 活性以支持肿瘤抑制基因的表达。
