FOXA2 promotes glutamine metabolism to facilitate the malignant development of bladder cancer by transcriptionally increasing GLS1 expression.

BACKGROUND

Forkhead box A2 (FOXA2) is found to be abnormally overexpressed in bladder cancer (BCa), but its role and underlying molecular mechanisms in BCa progression remain revealed.

METHODS

The expression levels of FOXA2, glutaminase 1 (GLS1), glutamine metabolism-related markers were examined using qRT-PCR and western blot. Glutamine metabolism was assessed by detecting glutamine uptake, intracellular glutamate, ATP, GSH and ROS levels. BCa cell proliferation, migration and invasion were analyzed by CCK8 assay, EdU assay, wound healing assay, and Transwell assay. The regulation of FOXA2 on GLS1 promoter was confirmed by dual-luciferase reporter assay and ChIP assay. Mice xenograft tumor models were constructed to evaluate the role of FOXA2 in BCa tumorigenesis.

RESULTS

FOXA2 expression was upregulated in BCa cells and its knockdown significantly decreased GLS1 expression. Silencing of FOXA2 inhibited BCa cell glutamine metabolism, thus suppressing cell proliferation and metastasis, and these effects were reversed by GLS1 overexpression. In terms of mechanism, FOXA2 increased the transcription and expression of GLS1 by binding to its promoter region. Animal study revealed that FOXA2 interference also reduced BCa tumorigenesis through decreasing GLS1 expression.

CONCLUSION

FOXA2 accelerated BCa cell proliferation and metastasis by promoting GLS1-mediated glutamine metabolism, providing a novel therapy target for BCa.