Critical Enzymatic Functions of FTO in Obesity and Cancer.
Critical Enzymatic Functions of FTO in Obesity and Cancer.
复制标题
FTO 在肥胖和癌症中的关键酶功能
DOI：
10.3389/fendo.2018.00396
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发表时间：
2018
影响因子：
5.2
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Deng X;Su R;Stanford S;Chen J
自2007年以来，全基因组关联研究（GWAS）已将脂肪量和肥胖相关蛋白（FTO）单核苷酸多态性（SNP）与人类体重增加和肥胖联系起来。虽然最近的一些研究表明，肥胖相关的SNPs在FTO影响肥胖易感性可能通过改变相邻基因的表达，如IRX 3和RPGRIP 1 L，而不是FTO本身，SNP风险基因型和增加FTO表达在人类血细胞和成纤维细胞之间的可靠联系已被报道。此外，多条证据表明，FTO确实在脂肪量、脂肪形成和体重的调节中发挥关键作用。流行病学研究还显示FTO SNP和超重/肥胖与各种类型癌症风险增加有很强的关联。FTO作为第一个被发现的信使RNA N6-甲基腺苷（m6 A）去甲基化酶，最近被证明在脂肪形成和肿瘤发生（特别是在白血病和胶质母细胞瘤的发展中）中发挥m6 A依赖性作用。鉴于FTO在癌症中的关键作用，靶向FTO的选择性和有效抑制剂的开发具有治疗癌症的潜力。本文综述了FTO在肥胖和癌症中的作用及其分子机制，并总结了FTO抑制剂的最新研究进展。
Fat mass and obesity-associated protein (FTO) single-nucleotide polymorphisms (SNPs) have been linked to increased body mass and obesity in humans by genome-wide association studies (GWAS) since 2007. Although some recent studies suggest that the obesity-related SNPs in FTO influence obesity susceptibility likely through altering the expression of the adjacent genes such as IRX3 and RPGRIP1L, rather than FTO itself, a solid link between the SNP risk genotype and the increased FTO expression in both human blood cells and fibroblasts has been reported. Moreover, multiple lines of evidence have demonstrated that FTO does play a critical role in the regulation of fat mass, adipogenesis, and body weight. Epidemiology studies also showed a strong association of FTO SNPs and overweight/obesity with increased risk of various types of cancers. As the first identified messenger RNA N6-methyladenosine (m6A) demethylase, FTO has been shown recently to play m6A-dependent roles in adipogenesis and tumorigenesis (especially in the development of leukemia and glioblastoma). Given the critical roles of FTO in cancers, the development of selective and effective inhibitors targeting FTO holds potential to treat cancers. This mini review discusses the roles and underlying molecular mechanisms of FTO in both obesity and cancers, and also summarizes recent advances in the development of FTO inhibitors.