N6 -methyladenosine RNA demethylase FTO regulates extracellular matrix-related genes and promotes pancreatic cancer cell migration and invasion

Pancreatic Cancer (PC) is a deadly disease, and its post-transcriptional gene regulation mechanism remains unclear. The abundant extracellular matrix (ECM) in PC plays an important role in tumor progression. This study is the first to focus on the role of N⁶ -methyladenosine (m⁶ A) RNA methylation, an emerging post-transcriptional regulatory mechanism, in the regulation of the ECM in PC. Here, we found that ADAMTS2, COL12A1, and THBS2 were associated with the prognosis of PC by comprehensive analysis of differentially expressed genes from two independent GEO expression profile datasets and m⁶ A-related genes in RMVar database (PAAD). GO and KEGG enrichment analysis found that these m⁶ A-related targets are chiefly functionally concentrated in the ECM region and participate in ECM signal transduction. Correlation analysis revealed that these genes can be regulated by the demethylase FTO. Cell Biology function assays showed that knockdown of FTO-inhibited PC cell abilities to migrate and invade in vitro. qRT-PCR and MeRIP experiments showed that after knockdown of FTO, the mRNA levels of ADAMTS2, COL12A1, and THBS2 and their m⁶ A modification levels were significantly reduced. These results indicate that m⁶ A RNA demethylation is associated with the regulation of ECM in PC. In conclusion, m⁶ A RNA demethylase FTO regulates ECM-related genes and promotes PC cell abilities to migrate and invade, our work provides a new perspective on the molecular mechanism of PC progression.