Effect of nucleolin-binding aptamer AS1411 on gene expression in 3T3 cells

AS1411 is a G-rich DNA aptamer that targets the multifunctional RNA-binding protein nucleolin. AS1411 has both antiproliferative and cell size-regulating activities and has been evaluated for clinical utility, reaching phase II trials as an anticancer agent. The mechanisms underlying the different activities of AS1411 are not completely understood and broad characterization of its molecular effects is lacking. Here, we used a multi-omics approach to profile transcriptome, proteome and lipidome changes in AS1411-treated NIH-3T3 cells, which increase in size in response to the aptamer. We found that AS1411 caused downregulation of cholesterol biosynthesis pathway enzymes at both mRNA and protein levels, without an accompanying drop in cellular cholesterol levels. In addition, AS1411 induced changes in several lipid classes, including increases in phospatidylethanolamine levels. Thus, nucleolin regulates lipid biosynthesis and homeostasis, potentially underlying its roles in cell proliferation and size control.