Network analysis reveals the molecular bases of statin pleiotropy that vary with genetic background

Abstract

Many approved drugs are pleiotropic, for example statins, whose main cholesterol lowering activity is complemented by anticancer and pro-diabetogenic mechanisms involving poorly characterized genetic interaction networks. We investigated these using the Saccharomyces cerevisiae genetic model where most genetic interactions known are limited to the statin-sensitive S288C genetic background. We therefore broadened our approach by investigating gene interactions to include two statin-resistant UWOPS87-2421 and Y55 genetic backgrounds. Networks were functionally focused by selection of HMG1 and BTS1 mevalonate pathway genes for detecting genetic interactions. Networks, multi-layered by genetic background, were analysed for modifying key genes using network centrality (degree, betweenness, closeness), pathway enrichment, functional community modules and gene ontology. Statin treatment induces the unfolded protein response and we found modifying genes related to dysregulated endocytosis and autophagic cell death. To translate results to human cells, human orthologues were searched for other drugs targets, thus identifying candidates for synergistic anticancer bioactivity.