YTHDC1 positively regulates PTEN expression and plays a critical role in cisplatin resistance of bladder cancer

Abstract

Activation of PI3K/AKT signalling by PTEN loss significantly enhances chemoresistance in bladder cancer. This study aims to evaluate PTEN regulation and identify targets that could be used to relieve chemoresistance. Expression of YTHDC1, γ-H2AX and PTEN were detected by IHC assay. Cell Counting Kit-8 assay, colony formation assay and tumour xenograft experiment evaluated cisplatin response. Flow cytometry and comet assay estimated cell apoptosis, cell cycle distribution and DNA repair capability. Quantitative real-time polymerase chain reaction, Western blot and RIP assay assessed binding properties between PTEN mRNA and YTHDC1. Silencing YTHDC1 in bladder cancer cells reduced PTEN expression and activated PI3K/AKT signalling by destabilizing PTEN mRNA in an m⁶ A-dependent manner. Low YTHDC1 expression indicated poor cisplatin sensitivity in bladder cancer patients. Reducing YTHDC1 expression promoted drug resistance to cisplatin, while over-expressing YTHDC1 promoted cisplatin sensitivity. Reducing YTHDC1 expression activated DNA damage response, which includes quicker cell cycle recovery, apoptosis evasion and an enhanced DNA repair capability, whereas these effects were attenuated when MK2206, a PI3K/AKT inhibitor was applied. We provide novel evidence that PTEN/PI3K/AKT signalling pathway could be regulated by YTHDC1 in an m⁶ A-dependent manner and highlight a critical role of YTHDC1 in cisplatin resistance of bladder cancer.