The Long Non-coding RNA TMPO-AS1 Promotes Bladder Cancer Growth and Progression via OTUB1-Induced E2F1 Deubiquitination

• Published in: Frontiers in oncology Vol. 11; p. 643163
• Main Authors: Zhang, Yeyu, Zhu, Yuxing, Xiao, Mengqing, Cheng, Yaxin, He, Dong, Liu, Jianye, Xiang, Liang, Gong, Lian, Wang, Zhanwang, Deng, Liping, Cao, Ke
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 18.03.2021
• Subjects: bladder cancer; E2F1; long non-coding RNA; Oncology; OTUB1; TMPO-AS1; E2F1; long non-coding RNA; bladder cancer; TMPO-AS1; OTUB1
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2021.643163

Background: Increasing evidence indicates that long non-coding RNAs (lncRNAs) play crucial roles in cancer tumorigenesis and progression. TMPO antisense RNA 1 (TMPO-AS1) has been found to be involved in several cancers by acting as a competing endogenous RNA. However, the potential roles of TMPO-AS1 in bladder cancer (BC) and the potential interactions with proteins remain poorly understood. Methods: The expression of the lncRNA TMPO-AS1 was evaluated via bioinformatic analysis and further validated by quantitative real-time PCR (qRT-PCR). Loss- and gain-of-function assays were performed to determine the biological functions of TMPO-AS1 in BC cell proliferation, migration, and invasion. Moreover, chromatin immunoprecipitation, Western blotting, and fluorescence in situ hybridization, as well as RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays, were conducted to explore the upstream and downstream molecules interacting with TMPO-AS1. Results: TMPO-AS1 is upregulated in BC. Functional experiments demonstrated that TMPO-AS1 promotes cell proliferation, migration, and invasion in BC and inhibits cell apoptosis in vivo and in vitro . Mechanically, E2F1 is responsible for TMPO-AS1 upregulation. Additionally, TMPO-AS1 facilitates the interaction of E2F1 with OTU domain-containing ubiquitin aldehyde binding 1 (OTUB1), leading to E2F1 deubiquitination and stabilization; therefore, TMPO-AS1 promotes BC malignant phenotypes. Furthermore, rescue experiments showed that TMPO-AS1 promotes BC growth in an E2F1-dependent manner. Conclusions: Our study is the first to uncover the novel TMPO-AS1/E2F1 positive regulatory loop important for the promotion of BC malignant behaviors. The TMPO-AS1/E2F1 loop should be considered in the quest for new BC therapeutic options.