METTL3-IGF2BP3-axis mediates the proliferation and migration of pancreatic cancer by regulating spermine synthase m6A modification

Abstract

Spermine synthase (<i>SMS</i>) is an enzyme participating in polyamine synthesis; however, its function and role in pancreatic cancer remains elusive. Here we report that <i>SMS</i> is upregulated in pancreatic cancer and predicts a worse overall survival and significantly promotes the proliferation and migration of pancreatic cancer cells. Excessive <i>SMS</i> reduces the accumulation of spermidine by converting spermidine into spermine, which activates the phosphorylation of serine/threonine kinase (AKT) and epithelial-mesenchymal transition (EMT) signaling pathway, thereby inhibiting pancreatic cancer cell proliferation and invasion. Moreover, <i>SMS</i> was identified as the direct target of both methyltransferase like 3 (<i>METTL3</i>) and insulin like growth factor 2 mRNA binding protein 3 (<i>IGF2BP3</i>), which directly bind to the m6A modification sites of <i>SMS</i> and inhibit mRNA degradation. Knockdown of <i>METTL3</i> or <i>IGF2BP3</i> significantly reduced the <i>SMS</i> protein expression and inhibited the migration of pancreatic cancer. We propose a novel regulatory mechanism in which the METTL3-IGF2BP3 axis mediates the mRNA degradation of SMS in an m6A-dependent manner to regulate spermine/spermidine conversion, which regulates AKT phosphorylation and EMT activation, thereby inducing tumor progression and migration in pancreatic cancer.