Image_2_The Long Non-coding RNA TMPO-AS1 Promotes Bladder Cancer Growth and Progression via OTUB1-Induced E2F1 Deubiquitination.TIF
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.
History
References
- https://doi.org//10.1016/S0140-6736(16)30512-8
- https://doi.org//10.3322/caac.21492
- https://doi.org//10.1016/j.cell.2018.07.036
- https://doi.org//10.1038/551S34a
- https://doi.org//10.1016/j.cell.2009.02.006
- https://doi.org//10.1038/nature08975
- https://doi.org//10.1038/s41467-018-06152-x
- https://doi.org//10.1186/s12943-019-1032-0
- https://doi.org//10.1016/j.eururo.2013.12.003
- https://doi.org//10.1186/s12943-017-0666-z
- https://doi.org//10.1128/MCB.00261-19
- https://doi.org//10.1002/cam4.3046
- https://doi.org//10.1186/s12935-020-01334-4
- https://doi.org//10.1016/j.cell.2010.06.040
- https://doi.org//10.1016/j.ejca.2005.08.005
- https://doi.org//10.1038/cddis.2017.205
- https://doi.org//10.1007/s10555-017-9697-6
- https://doi.org//10.3390/cells8070675
- https://doi.org//10.1158/0008-5472.CAN-15-0273
- https://doi.org//10.1093/nar/gkw965
- https://doi.org//10.1016/j.gpb.2019.09.006
- https://doi.org//10.1093/nar/gkx1188
- https://doi.org//10.1093/database/bav082
- https://doi.org//10.1038/s41467-019-09234-6
- https://doi.org//10.1093/bioinformatics/btt495
- https://doi.org//10.1016/j.biosystems.2015.10.004
- https://doi.org//10.1093/nar/gkx407
- https://doi.org//10.1002/prot.22555
- https://doi.org//10.1158/1078-0432.CCR-17-0419
- https://doi.org//10.1038/s41388-018-0223-2
- https://doi.org//10.4161/cc.5.12.2833
- https://doi.org//10.1038/cgt.2017.10
- https://doi.org//10.1200/JCO.2009.25.0977
- https://doi.org//10.1038/nrg2521
- https://doi.org//10.1002/jcb.29451
- https://doi.org//10.1158/0008-5472.CAN-16-2634
- https://doi.org//10.1126/science.1192002
- https://doi.org//10.1038/ncomms9704
- https://doi.org//10.1111/jgh.15362
- https://doi.org//10.1016/j.bbrc.2019.06.088
- https://doi.org//10.1016/j.biocel.2020.105702
- https://doi.org//10.1186/s13046-018-0945-6
- https://doi.org//10.1038/s41419-018-0275-9
- https://doi.org//10.1186/s13046-020-01725-5
- https://doi.org//10.1038/nrc2696
- https://doi.org//10.1007/s00018-020-03678-6
- https://doi.org//10.1158/1078-0432.CCR-16-0742
CC BY 4.0