Wang Zhenyu, Sun Huamin, Zhu Hua, Gu Donghua, Chen Xinfeng, Pan Yongsheng, Zheng Bing, Yang Dongrong
Department of Urology, The Second Affiliated Hospital of Soochow University, Jiangsu, China.
Department of Urology, The Second Affiliated Hospital of Nantong University, Jiangsu, China.
Turk J Biol. 2022 Oct 13;46(6):426-438. doi: 10.55730/1300-0152.2629. eCollection 2022.
Fat mass and obesity-associated protein (FTO) is a demethylase and plays a vital role in various cancers. However, the regulation mechanism of FTO in prostate cancer (PCa) remains unclear. This study aimed to elucidate the mechanism of FTO in PCa. The function and mechanism of FTO-mediated in PCa were determined by gain-of-function assays and RNA-seq. We found that FTO expression in PCa tissues and two PCa cell lines were significantly lower than that in adjacent tissues and normal cell line. PCa cells after overexpression of FTO showed a significant lower in proliferation, migration, and invasion capabilities. RNA-seq displayed that FTO overexpression altered transcriptome landscape in Du145 and PC-3 cells, particularly upregulating EGR2 expression. FTO overexpression induced differential expression genes, including MYLK2, DNA2, CDK, and CDC (6, 7, 20, 25, and 45), which were mainly enriched in adjustment of cell cycle and growth pathways. Furthermore, FTO overexpression significantly reduced the EGR2 methylation level. Arresting the proliferation, migration, and invasion of Du145 cells induced by FTO overexpression was significantly rescued by EGR2 knockdown. FTO overexpression also significantly inhibited tumor growth and promoted EGR2 protein expression. Taken together, FTO suppresses PCa progression by regulating EGR2 methylation. We uncovered a novel regulatory mechanism of FTO in PCa and provide a new potential therapeutic target for PCa.
脂肪量和肥胖相关蛋白（FTO）是一种去甲基化酶，在多种癌症中发挥着至关重要的作用。然而，FTO在前列腺癌（PCa）中的调控机制仍不清楚。本研究旨在阐明FTO在PCa中的作用机制。通过功能获得实验和RNA测序确定了FTO在PCa中介导的功能和机制。我们发现，PCa组织和两种PCa细胞系中FTO的表达明显低于相邻组织和正常细胞系。FTO过表达后的PCa细胞在增殖、迁移和侵袭能力方面显著降低。RNA测序显示，FTO过表达改变了Du145和PC-3细胞中的转录组格局，特别是上调了EGR2的表达。FTO过表达诱导了差异表达基因，包括MYLK2、DNA2、CDK以及CDC（6、7、20、25和45），这些基因主要富集在细胞周期和生长途径的调节中。此外，FTO过表达显著降低了EGR2的甲基化水平。通过敲低EGR2可显著挽救FTO过表达诱导的Du145细胞的增殖、迁移和侵袭的抑制。FTO过表达还显著抑制肿瘤生长并促进EGR2蛋白表达。综上所述，FTO通过调节EGR2甲基化抑制PCa进展。我们揭示了FTO在PCa中的一种新的调控机制，并为PCa提供了一个新的潜在治疗靶点。
