PTEN失调可激活PI3K/AKT信号通路，从而显著增强膀胱癌化疗耐药性。本研究旨在评估PTEN调节，并确定可用于缓解化疗耐药性的靶点。采用免疫组化检测了YTHDC1、γ-H2AX和PTEN的表达。细胞计数试剂盒-8、集落形成实验和肿瘤异种移植实验评估了顺铂的反应。流式细胞仪和彗星实验评估细胞凋亡、细胞周期分布和DNA修复能力。定量实时聚合酶链式反应、Western印迹和RIP实验评估PTEN mRNA和YTHDC1之间的结合特性。在膀胱癌细胞中沉默YTHDC1可降低PTEN表达，并以m6A依赖的方式破坏PTEN mRNA，从而激活PI3K/AKT信号通路。低YTHDC1表达暗示膀胱癌患者顺铂敏感性较差。降低YTHDC1表达促进顺铂耐药，而过度表达YTHDC1则促进顺铂敏感性。降低YTHDC1表达激活DNA损伤响应，包括更快的细胞周期恢复、逃避细胞凋亡和增强的DNA修复能力，而这些效应在应用PI3K/AKT抑制剂MK2206时被减弱。我们提供了PTEN/PI3K/AKT信号通路可以通过YTHDC1以m6A依赖的方式调节的新证据，并强调了YTHDC1在膀胱癌顺铂耐药性中的关键作用。©2023作者。由北京干细胞与再生医学研究所和约翰威利子公司发表的《细胞增殖》杂志。

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.© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.