Investigation into antisense gene silencing of the CYP17A1 gene locus in advanced prostate cancer (360G-Wellcome-211604_Z_18_Z)

Epigenetic lesions act collaboratively as master regulators of gene expression and thus oncogenesis. This project will address the relationship between two epigenetic aberrations, DNA methylation and non-coding RNA. Metastatic prostate cancer is fatal. Whilst tumours initially respond to endocrine therapy, resistance inevitable ensues in the form of castration-resistant disease. One of the most promising new therapeutic agents in recent years, is CYP17 inhibitor, abiraterone, which blocks adrenal production of androgens. Mechanisms of resistance to abiraterone are unknown. Previous research in our laboratory identified intragenic methylation of the CYP17A1 gene is associated with poorer overall survival. The aim of this project is to determine whether intragenic methylation of CYP17A1 serves to silence the CYP17A1 anti-sense gene, thus leading to elevated expression of the CYP17 enzyme and higher production of testosterone. This will be carried out through a series of cell culture experiments of prostate cancer cell lines to determine expression of both genes and the effect of overexpression of the antisense transcript on endogenous CYP17A1 expression. Pharmacological demethethylation will be employed to establish a relationship between CYP17A1 methylation and expression. Ultimately, this work could help personalize cancer medicine through development of a predictive biomarker for abiraterone.