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 (m6A) 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 m6A‐related genes in RMVar database (PAAD). GO and KEGG enrichment analysis found that these m6A‐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 m6A modification levels were significantly reduced. These results indicate that m6A RNA demethylation is associated with the regulation of ECM in PC. In conclusion, m6A 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. We identified, for the first time, the important role of m6A modification in the regulation of ECM related molecules in pancreatic cancer (PC). Our data revealed that ADAMTS2, COL12A1, and THBS2 may be involved in PC metastasis and progression and that this role is regulated by the m6A demethylation transferase FTO. These molecules hold promise as novel biomarkers for clinical prognosis in PC and may be served as potential therapeutic targets of PC, and this study provides a new perspective for the development of therapeutic strategies for PC.