Androgen receptor‐regulated circFNTA activates KRAS signaling to promote bladder cancer invasion

The androgen receptor (AR) has been linked to bladder cancer (BCa) progression, but if this involves circular RNAs (circRNAs) remains unclear. Here, we find that AR alters the levels of circRNA‐FNTA (circFNTA) to increase BCa cell invasion and chemo‐resistance. Mechanistically, AR represses the RNA editing gene ADAR2 via direct binding to its 5′ promoter region to increase circFNTA levels, which then sponges the microRNA miR‐370‐3p to increase the expression of its host gene FNTA. This AR‐mediated ADAR2/circFNTA/miR‐370‐3p/FNTA pathway then activates KRAS signaling to alter BCa cell invasion and chemo‐sensitivity to cisplatin. A clinical BCa sample survey shows that circFNTA expression is elevated in BCa tissues, and results from a BCa mouse model indicate that depletion of circFNTA leads to the suppression of BCa metastases and increased cisplatin chemo‐sensitivity. Together, based on our results using multiple BCa cell lines and an in vivo mouse model we suggest that targeting this newly identified AR/ADAR2/circFNTA/miR‐370‐3p/FNTA/KRAS axis may lead to the development of therapies to suppress BCa metastasis and to increase its chemo‐sensitivity. Synopsis The androgen receptor‐regulated circFNTA alters bladder cancer invasion and chemo‐resistance via modulating the miR‐370‐3p/FNTA/KRAS axis. Targeting this signaling pathway might establish novel therapies to suppress bladder cancer progression. The androgen receptor represses the RNA editing gene ADAR2 to increase circFNTA expression. circFNTA sponges miR‐370‐3p to increase the expression of its host gene FNTA. AR‐mediated ADAR2/circFNTA/miR‐370‐3p/FNTA signaling activates KRAS to alter cell invasion and chemo‐sensitivity. Graphical Abstract The androgen receptor‐regulated circFNTA alters bladder cancer invasion and chemo‐resistance via modulating the miR‐370‐3p/FNTA/KRAS axis. Targeting this signaling pathway might establish novel therapies to suppress bladder cancer progression.