Abstract：
Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase and plays critical oncogenic roles in multiple cancers. Here we show that FTO is an effective target in hepatocellular carcinoma (HCC). FTO is highly expressed in patients with HCC. Genetic depletion of Fto dramatically attenuated HCC progression in mice. Pharmacological inhibition of FTO by FB23/FB23-2 markedly suppressed the proliferation and migration of HCC cell lines in vitro and inhibited HCC tumorigenicity in xeno-transplanted mice. Mechanistically, FB23-2 suppressed the expression of Erb-b2 receptor tyrosine kinase 3 (ERBB3) and human tubulin beta class Iva (TUBB4A) by increasing the m6A level in these mRNA transcripts. The decrease in ERBB3 expression resulted in the inhibition of Akt-mTOR signaling, which subsequently impaired the proliferation and survival of HCC cells. Moreover, FB23-2 disturbed the stability of the tubulin cytoskeleton, whereas overexpression of TUBB4A rescued the migration of HCC cells. Collectively, our study demonstrates that FTO plays a critical role in HCC by maintaining the proliferation and migration of cells and highlights the potential of FTO inhibitors for targeting HCC.
摘要：
脂肪质量和肥胖相关蛋白（FTO）是一种N6-甲基腺苷（m6A）脱甲基酶，在多种癌症中起着重要的致癌作用。在这里，我们表明FTO是肝细胞癌（HCC）的有效靶标。FTO在HCC患者中高表达。Fto的遗传耗竭显着减弱了小鼠的HCC进展。FB23/FB23-2对FTO的药理抑制作用在体外显着抑制了HCC细胞系的增殖和迁移，并抑制了异种移植小鼠的HCC致瘤性。机械上,FB23-2通过增加这些mRNA转录物中的m6A水平来抑制Erb-b2受体酪氨酸激酶3（ERBB3）和人微管蛋白βIva类（TUBB4A）的表达。ERBB3表达的减少导致Akt-mTOR信号的抑制,这随后损害了肝癌细胞的增殖和存活。此外，FB23-2扰乱了微管蛋白细胞骨架的稳定性，而TUBB4A的过表达拯救了HCC细胞的迁移。总的来说，我们的研究表明,FTO通过维持细胞的增殖和迁移在HCC中起关键作用,并突出了FTO抑制剂靶向HCC的潜力.
