RNA N6-methyladenosine demethylase FTO promotes pancreatic cancer progression by inducing the autocrine activity of PDGFC in an m6A-YTHDF2-dependent manner

Abstract

RNA N6-methyladenosine (m6A) is an emerging regulator of mRNA modifications and represents a novel player in tumorigenesis. Although it has functional significance in both pathological and physiological processes, the role of m6A modification in pancreatic ductal cancer (PDAC) remains elusive. Here, we showed that high fat mass and obesity-associated gene (FTO) expression was associated with a poor prognosis in PDAC patients and that suppression of FTO expression inhibited cell proliferation. Here, m6A sequencing (m6A-seq) was performed to screen genes targeted by FTO. The effects of FTO stimulation on the biological characteristics of pancreatic cancer cells, including proliferation and colony formation, were investigated in vitro and in vivo. The results indicate that FTO directly targets platelet-derived growth factor C (PDGFC) and stabilizes its mRNA expression in an m6A-YTHDF2-dependent manner. m6A-methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR), RNA immunoprecipitation (RIP), and luciferase reporter assays were employed to validate the specific binding of FTO to PDGFC. PDGFC upregulation led to reactivation of the Akt signaling pathway, promoting cell growth. Overall, our study reveals that FTO downregulation leads to increased m6A modifications in the 3ʹ UTR of PDGFC and then modulates the degradation of its transcriptional level in an m6A-YTHDF2-dependent manner, highlighting a potential therapeutic target for PDAC treatment and prognostic prediction.