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Genome-wide RNAi analysis reveals that simultaneous inhibition of specific mevalonate pathway genes potentiates tumor
Aleksandra A Pandyra1,2,3, Peter J Mullen1, Carolyn A Goard1,2
1Princess Margaret Cancer Centre, Toronto, ON, Canada.
Abstract:
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 this pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), are promising agents currently being evaluated in 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 of the MVA pathway were amongst the top-scoring targets, including sterol regulatory element binding transcription factor 2 (SREBP2), 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1) and geranylgeranyl diphosphate synthase 1 (GGPS1). Each gene was independently validated and shown to significantly sensitize A549 cells to statin-induced apoptosis when knocked down. SREBP2 knockdown in lung and breast cancer cells completely abrogated the fluvastatin-induced upregulation of sterol-responsive genes HMGCR and HMGCS1. Knockdown of SREBP2 alone did not affect three-dimensional growth of lung and breast cancer cells, yet in combination with fluvastatin cell growth was disrupted. Taken together, these results show that directly targeting multiple levels of the MVA pathway, including blocking the sterol-feedback loop initiated by statin treatment, is an effective and targetable anti-tumor strategy.
Insights
Targeting the mevalonate pathway with statins shows anti-cancer promise. Knocking down key genes like SREBP2 enhances statin-induced cancer cell death, revealing a new therapeutic strategy.
Area of Science:
- Biochemistry
- Cancer Biology
- Metabolic Pathways
Background:
- The mevalonate (MVA) pathway is frequently dysregulated in cancers, indicating tumor reliance on this metabolic route.
- Statins, inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), are being investigated for their anti-cancer potential.
Purpose of the Study:
- To identify novel targets that enhance statin-induced apoptosis when silenced.
- To explore the role of MVA pathway genes in cancer cell sensitivity to statins.
Main Methods:
- A pooled genome-wide short hairpin RNA (shRNA) screen was employed to identify genes potentiating statin-induced apoptosis.
- Key MVA pathway genes, including SREBP2, HMGCS1, and GGPS1, were validated through knockdown experiments.
- The effect of SREBP2 knockdown on statin-induced gene expression and cancer cell growth was assessed.
Main Results:
- Genes within the MVA pathway, notably SREBP2, HMGCS1, and GGPS1, were identified as top-scoring targets in the screen.
- Knockdown of these genes significantly sensitized A549 cancer cells to statin-induced apoptosis.
- SREBP2 knockdown abrogated fluvastatin-induced upregulation of HMGCR and HMGCS1 and disrupted cancer cell growth in combination with fluvastatin.
Conclusions:
- Targeting multiple points in the MVA pathway, including the sterol-feedback loop, represents a viable anti-tumor strategy.
- SREBP2 is a critical regulator in the MVA pathway, and its inhibition potentiates statin efficacy against cancer cells.
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