JAZF1: A Master Metabolic Regulator of Sensitivity to a Polyamine Targeted Therapy.

Identifying and leveraging unique points of metabolic dysregulation in different disease settings is vital for safe and effective incorporation of metabolism-targeted therapies in the clinic. Additionally, it has been shown identification of master metabolic transcriptional regulators of individual metabolic pathways, and how they relate to the disease in question, may offer the key to understanding therapeutic response. In prostate cancer, we have previously demonstrated polyamine biosynthesis and the methionine cycle were targetable metabolic vulnerabilities. However, the master metabolic transcriptional regulators of these pathways, and how they affect treatment, have yet to be explored. We sought to characterize differential sensitivity of prostate cancer to polyamine and methionine targeted therapies by identifying novel master metabolic transcriptional regulators. We began by developing a gene signature from patient samples, which can predict response to metabolic therapy, and further uncovered a master metabolic transcriptional regulator, JAZF1. We characterized the effects of JAZF1 overexpression on prostate cancer cells, basally and in the context of treatment, by assessing mRNA levels, proliferation, colony formation capability, and key metabolic processes. Lastly, we confirmed the relevance of our findings in large publicly available cohorts of prostate cancer patient samples. We demonstrated differential sensitivity to polyamine and methionine therapies and identified JAZF1 as a master metabolic transcriptional regulator of this response. Implications: We have shown JAZF1 can alter sensitivity of cells and its expression can segregate patient populations into those that do, or do not highly express polyamine genes, leading to better prediction of response to a polyamine targeting therapy.