m⁶A RNA demethylase FTO promotes the growth, migration and invasion of pancreatic cancer cells through inhibiting TFPI-2

Pancreatic cancer (PC) is one of the most fatal cancers with a very poor prognosis. Here, we found that N⁶-methyladenosine (m⁶A) RNA demethylase fat mass and obesity-related protein (FTO) promote the growth, migration and invasion of PC. FTO expression level is increased in human PC and is associated with poor prognosis of PC patients. Knockdown of FTO increases m⁶A methylation of TFPI-2 mRNA in PC cells, thereby increasing mRNA stability via the m⁶A reader YTHDF1, resulting in up-regulation of TFPI-2 expression, and inhibits PC proliferation, colony formation, sphere formation, migration and invasion <i>in vitro</i>, as well as tumour growth <i>in vivo</i>. Rescue assay further confirms that FTO facilitates cancer progression by reducing the expression of TFPI-2. Mechanistically, FTO promotes the progression of PC at least partially through reducing m⁶A/YTHDF1 mediated TFPI-2 mRNA stability. Our findings reveal that FTO, as an m⁶A demethylase, plays a critical role in promoting PC growth, migration and invasion, suggesting that FTO may be a potential therapeutic target for treating PC.