Gene Regulation Network Analysis on Human Prostate Orthografts Highlights a Potential Role for the JMJD6 Regulon in Clinical Prostate Cancer

SIMPLE SUMMARY: Prostate cancer is a very common malignancy worldwide. Treatment resistant prostate cancer poses a big challenge to clinicians and is the second most common cause of premature death in men with cancer. Gene expression analysis has been performed on clinical tumours but to date none of the gene expression-based biomarkers for prostate cancer have been successfully integrated to into clinical practice to improve patient management and treatment choice. We applied a novel laboratory prostate cancer model to mimic clinical hormone responsive and resistant prostate cancer and tested whether a network of genes similarly regulated by transcription factors (gene products that control the expression of target genes) are associated with patient outcome. We identified regulons (networks of genes similarly regulated) from our preclinical prostate cancer models and further evaluated the top ranked JMJD6 gene related regulated network in three independent clinical patient cohorts. ABSTRACT: Background: Prostate cancer (PCa) is the second most common tumour diagnosed in men. Tumoral heterogeneity in PCa creates a significant challenge to develop robust prognostic markers and novel targets for therapy. An analysis of gene regulatory networks (GRNs) in PCa may provide insight into progressive PCa. Herein, we exploited a graph-based enrichment score to integrate data from GRNs identified in preclinical prostate orthografts and differentially expressed genes in clinical resected PCa. We identified active regulons (transcriptional regulators and their targeted genes) associated with PCa recurrence following radical prostatectomy. Methods: The expression of known transcription factors and co-factors was analysed in a panel of prostate orthografts (n = 18). We searched for genes (as part of individual GRNs) predicted to be regulated by the highest number of transcriptional factors. Using differentially expressed gene analysis (on a per sample basis) coupled with gene graph enrichment analysis, we identified candidate genes and associated GRNs in PCa within the UTA cohort, with the most enriched regulon being JMJD6, which was further validated in two additional cohorts, namely EMC and ICGC cohorts. Cox regression analysis was performed to evaluate the association of the JMJD6 regulon activity with disease-free survival time in the three clinical cohorts as well as compared to three published prognostic gene signatures (TMCC11, BROMO-10 and HYPOXIA-28). Results: 1308 regulons were correlated to transcriptomic data from the three clinical prostatectomy cohorts. The JMJD6 regulon was identified as the top enriched regulon in the UTA cohort and again validated in the EMC cohort as the top-ranking regulon. In both UTA and EMC cohorts, the JMJD6 regulon was significantly associated with cancer recurrence. Active JMJD6 regulon also correlated with disease recurrence in the ICGC cohort. Furthermore, Kaplan–Meier analysis confirmed shorter time to recurrence in patients with active JMJD6 regulon for all three clinical cohorts (UTA, EMC and ICGC), which was not the case for three published prognostic gene signatures (TMCC11, BROMO-10 and HYPOXIA-28). In multivariate analysis, the JMJD6 regulon status significantly predicted disease recurrence in the UTA and EMC, but not ICGC datasets, while none of the three published signatures significantly prognosticate for cancer recurrence. Conclusions: We have characterised gene regulatory networks from preclinical prostate orthografts and applied transcriptomic data from three clinical cohorts to evaluate the prognostic potential of the JMJD6 regulon.