Zou Libin, Chen Wenbin, Zhou Xumin, Yang Taowei, Luo Junqi, Long Zining, Wu Jun, Lv Daojun, Mao Xiangming, Cen Shengren
Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of Urology, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Cell Death Discov. 2022 Apr 9;8(1):184. doi: 10.1038/s41420-022-01003-7.
The fat mass and obesity-associated protein (FTO) is an N6-Methyladenosine (m6A) demethylase, which has been revealed to play critical roles in tumorigenesis. However, its role in the development and progression of prostate cancer (PCa) remains poorly understood. Here, we aimed to investigate the function and clinical relevance of FTO in PCa. Our results demonstrated that FTO was notably downregulated in PCa tissues compared with the paired normal tissues. In addition, the decreased expression of FTO was correlated with poor prognosis of PCa. Functional experiments showed that depletion of FTO promoted the proliferation and metastasis of PCa both in vitro and in vivo. Conversely, ectopic expression of FTO exhibited the opposite effects. Combined with RNA-sequencing, MeRIP-RT-qPCR, and mRNA stability assays indicated chloride intracellular channel 4(CLIC4) was a functional target of FTO-mediated m6A modification. FTO depletion significantly increased the m6A level of CLIC4 mRNA and then reduced the mRNA stability. In conclusion, our findings suggest that FTO suppresses PCa proliferation and metastasis through reducing the degradation of CLIC4 mRNA in an m6A dependent manner. FTO may be used as a promising novel therapeutic target and prognostic evaluation biomarker for PCa.
脂肪量与肥胖相关蛋白（FTO）是一种N6-甲基腺苷（m6A）去甲基化酶，已被揭示在肿瘤发生中起关键作用。然而，其在前列腺癌（PCa）发生发展中的作用仍知之甚少。在此，我们旨在研究FTO在PCa中的功能及临床相关性。我们的结果表明，与配对的正常组织相比，FTO在PCa组织中显著下调。此外，FTO表达降低与PCa的不良预后相关。功能实验表明，FTO缺失在体外和体内均促进了PCa的增殖和转移。相反，FTO的异位表达则表现出相反的效果。结合RNA测序、MeRIP-RT-qPCR和mRNA稳定性分析表明，氯离子细胞内通道4（CLIC4）是FTO介导的m6A修饰的功能靶点。FTO缺失显著增加了CLIC4 mRNA的m6A水平，进而降低了mRNA稳定性。总之，我们的研究结果表明，FTO通过以m6A依赖的方式减少CLIC4 mRNA的降解来抑制PCa的增殖和转移。FTO可能作为PCa一种有前景的新型治疗靶点和预后评估生物标志物。
