Jarid2 通过调节 PTEN/AKT 信号通路促进膀胱癌的进展。

Jarid2 enhances the progression of bladder cancer through regulating PTEN/AKT signaling.

机构信息

Department of Urology, Affiliated Hangzhou First People's Hospital, School of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province 310006, China.

Department of Urology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou City, Zhejiang Province 310014, China.

出版信息

Life Sci. 2019 Aug 1;230:162-168. doi: 10.1016/j.lfs.2019.05.053. Epub 2019 May 21.

DOI:10.1016/j.lfs.2019.05.053

PMID:31125562

Abstract

AIMS

Jumonji AT-rich interactive domain 2 (Jarid2) is an interacting component of PRC2 which catalyzes methylation of H3K27 (H3K27me3) and causes the downregulation of PTEN. In the present study, we aimed to explore whether Jarid2 could interact with H3K27me3 to regulate PTEN expression in bladder cancer.

MAIN METHODS

Jarid2 expression in bladder cancer tissues and cells were determined by western blotting and RT-PCR. CCK-8, flow cytometry, transwell chamber and in vivo xenograft assays were performed to assess cell growth, apoptosis, migration and tumorigenesis, respectively. Chromatin immunoprecipitation (ChIP) assay was used to assess the methylation of PTEN.

KEY FINDINGS

Jarid2 expression was increased in bladder cancer tissues and cells. Downregulation of Jarid2 with shRNA transfection obviously inhibited the proliferation, migration and tumorigenesis of bladder cancer T24 and HT-1376 cells and induced cell apoptosis. Jarid2 downregulation decreased the expression of p-AKT and increased PTEN expression. Besides, Jarid2 down-regulation repressed the epithelial-mesenchymal transition (EMT), whereas knockdown of PTEN impaired this effect. Moreover, upregulation of Jarid2 increased the combination of PTEN promoter and H3K27me3, and 5-aza-CdR rescued it. Meanwhile, 5-aza-CdR administration abolished Jarid2 roles in the promotion of EMT process and AKT activation, as well as the reduction of PTEN expression.

SIGNIFICANCE

Overall, the present study elaborated that Jarid2 facilitated the progression of bladder cancer through H3K27me3-mediated PTEN downregulation and AKT activation, which might provide a new mechanism for Jarid2 in promoting bladder cancer progression.

摘要

目的

组蛋白赖氨酸 N-甲基转移酶家族成员 2（Jarid2）是 PRC2 的相互作用成分，可催化 H3K27（H3K27me3）甲基化，导致 PTEN 的下调。在本研究中，我们旨在探讨 Jarid2 是否可以与 H3K27me3 相互作用来调节膀胱癌中的 PTEN 表达。

主要方法

通过 Western blot 和 RT-PCR 检测膀胱癌组织和细胞中的 Jarid2 表达。通过 CCK-8、流式细胞术、Transwell 室和体内异种移植实验分别评估细胞生长、凋亡、迁移和肿瘤发生情况。染色质免疫沉淀（ChIP）实验用于评估 PTEN 的甲基化。

主要发现

Jarid2 在膀胱癌组织和细胞中表达增加。用 shRNA 转染下调 Jarid2 明显抑制膀胱癌 T24 和 HT-1376 细胞的增殖、迁移和肿瘤发生，并诱导细胞凋亡。Jarid2 下调降低了 p-AKT 的表达，增加了 PTEN 的表达。此外，Jarid2 下调抑制了上皮-间充质转化（EMT），而敲低 PTEN 则削弱了这一作用。此外，上调 Jarid2 增加了 PTEN 启动子与 H3K27me3 的结合，而 5-氮杂胞苷（5-aza-CdR）挽救了这一作用。同时，5-aza-CdR 给药消除了 Jarid2 在促进 EMT 过程和 AKT 激活以及降低 PTEN 表达中的作用。