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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
LncRNA-SLC16A1-AS1 induces metabolic reprogramming during Bladder Cancer progression as target and co-activator of E2F1
Theranostics, Volume 10, No. 21, Year 2020
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Description
Long non-coding RNAs (lncRNAs) have emerged as integral components of E2F1-regulated gene regulatory networks (GRNs), but their implication in advanced or treatment-refractory malignancy is unknown. Methods: We combined high-throughput transcriptomic approaches with bioinformatics and structure modeling to search for lncRNAs that participate in E2F1-activated prometastatic GRNs and their phenotypic targets in the highly-relevant case of E2F1-driven aggressive bladder cancer (BC). RNA immunoprecipitation was performed to verify RNA-protein interactions. Functional analyses including qRT-PCR, immunoblotting, luciferase assays and measurement of extracellular fluxes were conducted to validate expression and target gene regulation. Results: We identified E2F1-responsive lncRNA-SLC16A1-AS1 and its associated neighboring protein-coding gene, SLC16A1/MCT1, which both promote cancer invasiveness. Mechanistically, upon E2F1-mediated co-transactivation of the gene pair, SLC16A1-AS1 associates with E2F1 in a structure-dependent manner and forms an RNA-protein complex that enhances SLC16A1/MCT1 expression through binding to a composite SLC16A1-AS1:E2F1-responsive promoter element. Moreover, SLC16A1-AS1 increases aerobic glycolysis and mitochondrial respiration and fuels ATP production by fatty acid β-oxidation. These metabolic changes are accompanied by alterations in the expression of the SLC16A1-AS1:E2F1-responsive gene PPARA, a key mediator of fatty acid β-oxidation. Conclusions: Our results unveil a new gene regulatory program by which E2F1-induced lncRNA-SLC16A1-AS1 forms a complex with its transcription factor that promotes cancer metabolic reprogramming towards the acquisition of a hybrid oxidative phosphorylation/glycolysis cell phenotype favoring BC invasiveness. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Authors & Co-Authors
Marquardt, Stephan
Germany, Rostock
Universität Rostock Uniklinikum Und Medizinische Fakultät
Gupta, Shailendra Kumar
Germany, Rostock
Universität Rostock
Engelmann, David
Germany, Rostock
Universität Rostock Uniklinikum Und Medizinische Fakultät
Singh, Krishan Pal
Germany, Rostock
Universität Rostock
Wolkenhauer, Olaf
Germany, Rostock
Universität Rostock
Spitschak, Alf
Germany, Rostock
Universität Rostock Uniklinikum Und Medizinische Fakultät
Pützer, Brigitte M.
Germany, Rostock
Universität Rostock Uniklinikum Und Medizinische Fakultät
Germany, Rostock
Universität Rostock
Statistics
Citations: 53
Authors: 7
Affiliations: 4
Identifiers
Doi:
10.7150/thno.44176
ISSN:
18387640
Research Areas
Cancer
Genetics And Genomics
Health System And Policy
Noncommunicable Diseases