The influence of an epigenetic drift on treatment decisions in elderly prostate cancer patients

• Applicant: Dr. Oliver Hahn
• Subject Area: Reproductive Medicine, Urology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 511994031

Epigenetic alterations are one of the hallmarks of the aging process and can directly influence susceptibility to cancer therapies. Histone H3 lysine 27 tri-methylation (H3K27me3) is a repressive histone mark inhibiting transcription. Previous studies have shown decrease of this mark in prostate cancer (PCA) patients of advanced age. In our workgroup, we correlated this decrease with resistance to new hormonal agents (NHAs) such as abiraterone by generating VCaP cells resistant to all NHAs currently on the market. We found resistance and changes in histone modification patterns to correlate in vitro with alterations in PCA lipid metabolism, specifically with decreased activity of the mevalonate pathway and increased lipid peroxidation. In this project, we will verify whether alterations in H3K27me3 levels correlate with the biological and chronological age of PCA patients, do have an impact on treatment decisions, and can be used to predict alterations in lipid metabolism and consecutively sensitivity to ferroptosis. For this, we will use both our cell culture model as well as a characterized cohort of 450 patients who underwent surgery for PCA in Göttingen. First, we will profile H3K27ac, H3K4me3, and H3K27me3 expression by immunohistochemistry in those patients and correlate the markers with a clinical follow-up. Next, we will stratify these patients based on age and H3K27me3 expression to then do RNA sequencing and lipidomic profiling from 40 selected cases. Furthermore, we will characterize occupancy patterns of all three histone modifications in vitro and validate them in our patient cohort. Based on these findings, we intend to establish a gene and lipid expression signature of aging PCA patients. In a next step, we will then characterize in vitro the influence of this signature on cellular energy metabolism by Seahorse assay measuring oxygen consumption rate, glycolytic activity, fatty acid oxidation, and total ATP levels. Based on these findings, we will then analyze the influence of these metabolic changes on Fe2+/Fe3+ levels and characterize the susceptibility of cells for ferroptosis-inducing compounds. Like this, we will not only provide stratification options for NHA treatment in aging patients but also give a deeper insight into fatty acid and iron metabolism, which might be exploited in future therapy.

• DFG Programme: Research Grants