Theranostics 2020; 10(21):9620-9643. doi:10.7150/thno.44176

Research Paper

LncRNA-SLC16A1-AS1 induces metabolic reprogramming during Bladder Cancer progression as target and co-activator of E2F1

Stella Logotheti1*, Stephan Marquardt1*, Shailendra K. Gupta3*, Christin Richter1*, Berdien A.H. Edelhäuser1, David Engelmann1, Julia Brenmoehl4, Christoph Söhnchen1, Nico Murr1, Michael Alpers1, Krishna P. Singh3, Olaf Wolkenhauer3, Dirk Heckl5, Alf Spitschak1, Brigitte M. Pützer1,2✉

1. Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, 18057 Rostock, Germany.
2. Department Life, Light & Matter, University of Rostock, 18059 Rostock, Germany.
3. Department of Systems Biology and Bioinformatics, University of Rostock, 18057 Rostock, Germany.
4. Leibniz Institute for Farm Animal Biology (FBN), Institute of Genome Biology, Signal Transduction Unit, 18196 Dummerstorf, Germany.
5. Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany.
*These authors contributed equally to this work.

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Citation:
Logotheti S, Marquardt S, Gupta SK, Richter C, Edelhäuser BAH, Engelmann D, Brenmoehl J, Söhnchen C, Murr N, Alpers M, Singh KP, Wolkenhauer O, Heckl D, Spitschak A, Pützer BM. LncRNA-SLC16A1-AS1 induces metabolic reprogramming during Bladder Cancer progression as target and co-activator of E2F1. Theranostics 2020; 10(21):9620-9643. doi:10.7150/thno.44176. Available from http://www.thno.org/v10p9620.htm

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Abstract

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.

Keywords: bladder cancer, E2F1, metabolic reprogramming, RNA-protein complex, SLC16A1-AS1