脂肪质量和肥胖相关蛋白（FTO）是一个去甲基酶，在各种癌症中扮演着重要的角色。然而，FTO在前列腺癌（PCa）中的调控机制尚不清楚。本研究旨在阐明FTO在PCa中的机制。通过功能增强实验和RNA-seq确定了FTO在PCa中介导的功能和机制。我们发现，在PCa组织和两株PCa细胞系中，FTO的表达明显低于相邻组织和正常细胞系。过表达FTO后，PCa细胞的增殖、迁移和侵袭能力明显降低。RNA-seq显示，FTO过表达改变了Du145和PC-3细胞中转录组的特征，尤其上调了EGR2的表达。FTO过表达诱导了差异表达基因，包括MYLK2、DNA2、CDK和CDC（6、7、20、25和45），主要富集于细胞周期和生长途径的调节。此外，FTO过表达显著降低了EGR2的甲基化水平。通过EGR2减少，FTO过表达对Du145细胞的增殖、迁移和侵袭抑制效果显著减弱。FTO过表达还显著抑制了肿瘤生长并促进了EGR2蛋白的表达。综上所述，FTO通过调节EGR2的甲基化来抑制PCa的进展。我们揭示了FTO在PCa中的新的调控机制，并提供了一个新的潜在治疗目标。

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.© TÜBİTAK.