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

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.

journal_name

Theranostics

journal_title

Theranostics

authors

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

doi

10.7150/thno.44176

subject

Has Abstract

pub_date

2020-07-29 00:00:00

pages

9620-9643

issue

21

issn

1838-7640

pii

thnov10p9620

journal_volume

10

pub_type

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