Antisense oligonucleotide targeting nicotinamide N-methyltransferase exhibits antitumor effects

Nicotinamide N-methyltransferase (NNMT) is one of the methyltransferase family genes. It consumes S-adenosyl-l-methionine (SAM), which is required for DNA methylation and histone methylation for epigenetic regulation, to produce 1-methylnicotinamide from nicotinamide, a source of NAD⁺, thus affecting energy metabolism and epigenetics. Recent studies have shown that <i>NNMT</i> is highly expressed in cancer tissues, mainly in the stroma, and worsens prognosis. Therefore, NNMT is attracting attention as a new target for cancer therapy. In this study, we generated 2',4'-BNA/LNA-modified gapmer phosphorothioate antisense oligonucleotides that inhibit <i>NNMT</i> expression and examined their antitumor effects. The antisense oligonucleotide candidates were finally narrowed down to eight sequences, and when they were examined for their inhibitory effect on <i>NNMT</i> expression in cancer cells, all of the sequences showed inhibitory effects. The most effective one was conjugated with a small molecule compound that targets the stroma of cancer tissues. The antitumor effect was examined in a mouse model of cancer cell transplantation, and the antitumor effect was enhanced in the group treated with the antisense oligonucleotide. These results indicate that <i>NNMT</i> antisense oligonucleotide drugs targeting the stroma are promising as novel anticancer agents.