Genome-wide RNAi analysis reveals that simultaneous inhibition of specific mevalonate pathway genes potentiates tumor cell death

摘要: The mevalonate (MVA) pathway is often dysregulated or overexpressed in many cancers suggesting tumor dependency on this classic metabolic pathway. Statins, which target the rate-limiting enzyme of pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), are promising agents currently being evaluated clinical trials for anti-cancer efficacy. To uncover novel targets that potentiate statin-induced apoptosis when knocked down, we carried out a pooled genome-wide short hairpin RNA (shRNA) screen. Genes MVA were amongst top-scoring targets, including sterol regulatory element binding transcription factor 2 (SREBP2), 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1) and geranylgeranyl diphosphate (GGPS1). Each gene was independently validated shown to significantly sensitize A549 cells down. SREBP2 knockdown lung breast cancer completely abrogated fluvastatin-induced upregulation sterol-responsive genes HMGCR HMGCS1. Knockdown alone did not affect three-dimensional growth cells, yet combination with fluvastatin cell disrupted. Taken together, these results show directly targeting multiple levels blocking sterol-feedback loop initiated by statin treatment, an effective targetable anti-tumor strategy.