Changes in Gene Transcription Underlying the Aberrant Citrate and Choline Metabolism in Human Prostate Cancer Samples

Abstract

Low concentrations of citrate and high concentrations of choline-containing compounds (ChoCC) are metabolic characteristics observed by magnetic resonance spectroscopy of prostate cancer tissue. The objective was to investigate the gene expression changes underlying these metabolic aberrations to find regulatory genes with potential for targeted therapies. Fresh frozen samples (n = 133) from 41 patients undergoing radical prostatectomy were included. Histopathologic evaluation was carried out for each sample before a metabolic profile was obtained with high-resolution magic angle spinning (HR-MAS) spectroscopy. Following the HR-MAS, RNA was extracted from the same sample and quality controlled before carrying out microarray gene expression profiling. A partial least square statistical model was used to integrate the data sets to identify genes whose expression show significant covariance with citrate and ChoCC levels. Samples were classified as benign, n = 35; cancer of low grade (Gleason score 6), n = 24; intermediate grade (Gleason score 7), n = 41; or high grade (Gleason score ≥ 8), n = 33. RNA quality was high with a mean RNA Integrity Number score of 9.1 (SD 1.2). Gene products predicting significantly a reduced citrate level were acetyl citrate lyase (ACLY, P = 0.003) and m-aconitase (ACON, P < 0.001). The two genes whose expression most closely accompanied the increase in ChoCC were those of phospholipase A2 group VII (PLA2G7, P < 0.001) and choline kinase α (CHKA, P = 0.002). By integrating histologic, transcriptomic, and metabolic data, our study has contributed to an expanded understanding of the mechanisms underlying aberrant citrate and ChoCC levels in prostate cancer.