We have performed a functional in vivo mutagenesis screen to identify genes that, when altered, cooperate with a heterozygous Pten mutation to promote prostate tumour formation. Two genes, Bzw2 and Eif5a2, which have been implicated in the process of protein translation, were selected for further validation. Using prostate organoid models, we show that either Bzw2 downregulation or EIF5A2 overexpression leads to increased organoid size and in vivo prostate growth. We show that both genes impact the PI3K pathway and drive a sustained increase in phospho-AKT expression, with PTEN protein levels reduced in both models. Mechanistic studies reveal that EIF5A2 is directly implicated in PTEN protein translation. Analysis of patient datasets identified EIF5A2 amplifications in many types of human cancer, including the prostate. Human prostate cancer samples in two independent cohorts showed a correlation between increased levels of EIF5A2 and upregulation of a PI3K pathway gene signature. Consistent with this, organoids with high levels of EIF5A2 were sensitive to AKT inhibitors. Our study identified novel genes that promote prostate cancer formation through upregulation of the PI3K pathway, predicting a strategy to treat patients with genetic aberrations in these genes particularly relevant for EIF5A2 amplified tumours.
Oncogene. 2024 Apr 23 [Epub ahead of print]
Jeffrey C Francis, Amy Capper, Alistair G Rust, Klea Ferro, Jian Ning, Wei Yuan, Johann de Bono, Stephen J Pettitt, Amanda Swain
Division of Cancer Biology, Institute of Cancer Research, London, SW3 6JB, UK., Genomics Facility, Institute of Cancer Research, London, UK., Tumour Modelling Facility, Institute of Cancer Research, London, SW3 6JB, UK., Institute of Cancer Research and Royal Marsden Hospital, London, UK., The CRUK Gene Function Laboratory, Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, SW3 6JB, UK., Division of Cancer Biology, Institute of Cancer Research, London, SW3 6JB, UK. .