Hu Bowen, Zhou Shijie, Hu Xuefeng, Zhang Hua, Lan Xiaorong, Li Mei, Wang Yunbing, Hu Qinsheng
Department of Orthopedics, Orthopedics Research Institute, West China Hospital, Sichuan University, Chengdu, China.
Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
J Cell Mol Med. 2021 Jul;25(13):5976-5987. doi: 10.1111/jcmm.16409. Epub 2021 May 16.
5'-Nucleotidase Domain Containing 2 (NT5DC2) is a novel oncoprotein, the regulatory effects of which have not been well characterized. This study aimed to investigate the expression profile and functional regulation of NT5DC2 and its potential interplay with TEAD4 in leiomyosarcoma (LMS). Bioinformatic analysis was conducted using data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) program. LMS cell lines SK-LMS-1 and SK-UT-1 were used for both in vitro and in vivo analysis. Results showed that NT5DC2 is aberrantly upregulated in LMS. Its overexpression was associated with unfavourable survival. Deletion of NT5DC2 significantly reduced the expression of cyclin B1, cyclin A2, cyclin E1 and CDK1 and increased G1 phase arrest in LMS cell lines, and suppressed their proliferation both in vitro and in vivo. NT5DC2 interacted with unpalmitoylated TEAD4, and this association reduced TEAD4 degradation via the ubiquitin-proteasome pathway. TRIM27 is a novel E3 ubiquitin ligase that induces K27/48-linked ubiquitination of unpalmitoylated TEAD4 at Lys278. TEAD4 inhibition significantly suppressed LMS cell growth both in vitro and in vivo. Dual-luciferase assay demonstrated that TEAD4 could bind to the NT5DC2 promoter and activate its transcription. Based on these findings, we infer that the NT5DC2-TEAD4 positive feedback loop plays an important role in LMS development and might serve as a potential therapeutic target.
含5'-核苷酸酶结构域2（NT5DC2）是一种新型癌蛋白，其调节作用尚未得到充分表征。本研究旨在探讨NT5DC2在平滑肌肉瘤（LMS）中的表达谱、功能调控及其与TEAD4的潜在相互作用。使用来自癌症基因组图谱（TCGA）和基因型-组织表达（GTEx）项目的数据进行生物信息学分析。LMS细胞系SK-LMS-1和SK-UT-1用于体外和体内分析。结果显示，NT5DC2在LMS中异常上调。其过表达与不良生存相关。NT5DC2的缺失显著降低了细胞周期蛋白B1、细胞周期蛋白A2、细胞周期蛋白E1和细胞周期蛋白依赖性激酶1的表达，并增加了LMS细胞系中的G1期阻滞，并在体外和体内均抑制了它们的增殖。NT5DC2与未棕榈酰化的TEAD4相互作用，这种关联减少了TEAD4通过泛素-蛋白酶体途径的降解。TRIM27是一种新型E3泛素连接酶，可诱导未棕榈酰化的TEAD4在赖氨酸278处发生K27/48连接的泛素化。TEAD4抑制在体外和体内均显著抑制了LMS细胞的生长。双荧光素酶测定表明，TEAD4可与NT5DC2启动子结合并激活其转录。基于这些发现，我们推断NT5DC2-TEAD4正反馈环在LMS发展中起重要作用，并可能作为潜在的治疗靶点。
