Azhati Baihetiya, Reheman Aerziguli, Dilixiati Diliyaer, Rexiati Mulati
Department of Urology, The First Affiliated Hospital of Xinjiang Medical University, No.137 South Carp Hill Road, Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Province, People's Republic of China.
Department of Operating Room, The First Affiliated Hospital of Xinjiang Medical University, No.137 South Carp Hill Road, Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Province, People's Republic of China.
Arch Biochem Biophys. 2023 Jun;741:109604. doi: 10.1016/j.abb.2023.109604. Epub 2023 Apr 18.
As one of the most important demethylases for RNA N6-methyladenosine (m6A) modifications, fat mass and obesity-associated protein (FTO) plays anti-cancer role during prostate cancer (PC), but it is still unclear the detailed molecular mechanisms. Here, this study verified that FTO inactivated the tumor-accelerating PI3K/Akt/mTOR pathway to hamper PC development through regulating the downstream miR-139-5p/zinc finger protein 217 (ZNF217) axis. Through performing clinical analysis, it was revealed that FTO was apparently ablated in the cancerous tissues compared to the normal tissues collected from PC patients, and patients with high-expressed FTO predicted a favorable prognosis. Functional experiments confirmed that overexpression of FTO suppressed cell proliferation, mitosis, epithelial-mesenchymal transition (EMT), tumorigenesis and lung metastasis both in vitro and in vivo. The following mechanical experiments verified that FTO stabilized miR-139-5p to increase its expression levels in a m6A-dependent manner, and elevated miR-139-5p induced degradation of ZNF217 through binding to ZNF217 mRNA, resulting in the inactivation of the PI3K/Akt/mTOR signal pathway. Finally, our rescuing experiments confirmed that overexpressed FTO-induced tumor-suppressing effects on PC cells were abrogated by miR-139-5p ablation and ZNF217 overexpression. Collectively, this study firstly validated that FTO exerted its anti-tumor effects in PC through regulating the miR-139-5p/ZNF217 axis in a m6A-dependent manner, providing novel biomarkers for the advancement of anti-cancer agents for PC treatment.
作为RNA N6-甲基腺苷（m6A）修饰最重要的去甲基化酶之一，脂肪量和肥胖相关蛋白（FTO）在前列腺癌（PC）中发挥抗癌作用，但其详细的分子机制仍不清楚。在此，本研究证实FTO通过调节下游miR-139-5p/锌指蛋白217（ZNF217）轴使促肿瘤的PI3K/Akt/mTOR通路失活，从而阻碍PC的发展。通过临床分析发现，与从PC患者收集的正常组织相比，癌组织中FTO明显缺失，FTO高表达的患者预后良好。功能实验证实，FTO的过表达在体外和体内均抑制细胞增殖、有丝分裂、上皮-间质转化（EMT）、肿瘤发生和肺转移。随后的机制实验证实，FTO以m6A依赖的方式稳定miR-139-5p以增加其表达水平，而升高的miR-139-5p通过与ZNF217 mRNA结合诱导ZNF217降解，导致PI3K/Akt/mTOR信号通路失活。最后，我们的挽救实验证实，miR-139-5p缺失和ZNF217过表达消除了FTO过表达诱导的对PC细胞的肿瘤抑制作用。总体而言，本研究首次证实FTO通过以m6A依赖的方式调节miR-139-5p/ZNF217轴在PC中发挥抗肿瘤作用，为开发用于PC治疗的抗癌药物提供了新的生物标志物。
