ZC3H4 Driven Prostate Tissue Remodeling Triggered by Maladaptive Metabolic and Signaling Pathways

PROJECT SUMMARY/ABSTRACT Pathologic changes in benign prostatic hyperplasia (BPH), an age-related condition, contribute to lower urinary tract symptom (LUTS) development through impingement of the urethra, alterations in smooth muscle tone, inflammation and fibrosis. However, the etiology that drives these pathophysiologic changes in aging men has not been fully elucidated. Current treatments for BPH/LUTS target either smooth muscle tone or androgen- dependent prostatic hyperplasia but many men develop resistance to these drugs. The lack of effective treatments for BPH/LUTS targeting the inflammatory and/or fibrotic component of this condition is attributed to the limited mechanistic information regarding the drivers of prostatic inflammation and fibrosis and their resulting impact on LUTS. We recently reported that selective mitochondrial dysfunction occurs in the prostate of men with BPH/LUTS (i.e., reduced activity of electron transport chain (ETC) Complex I (CI)) and drives a profibrotic phenotype in cultured prostatic stromal cells and in the prostate of mouse models of BPH/LUTS. We found that forcing human prostatic fibroblasts to predominantly rely on the ETC to generate ATP (i.e., by restricting glycolysis) influenced their attachment to the substratum. Under these conditions, prostatic fibroblasts undergo an anoikis program of cell death and initiated engagement in an adaptive response to support anoikis resistance as suggested by the clustering of detached cells. The anoikis resistance marker/transcription termination factor ZC3H4 is critical for prostate stromal cell adhesion in vitro and is down-regulated in the stromal and epithelial compartments of BPH, suggesting that it may play a role in BPH/LUTS pathogenesis. We hypothesize that restricting mitochondrial CI function in prostate cells heavily reliant on OXPHOS (i.e., normal physiological state of prostate stromal tissue or glycolytic-restricted stromal cells in culture) triggers cellular phenotypes (i.e., altered cell-cell adhesion/ECM attachment, senescence) that drive pathophysiologic changes associated with BPH/LUTS. This proposal seeks to elucidate mechanisms by which metabolic maladaptations associated with aging (e.g., reduced mitochondrial function) direct ZC3H4 to drive pathologic and pathophysiologic features of BPH/LUTS. Aim 1 will measure ZC3H4 expression in human prostate tissue and its function in prostate stromal cells. Aim 2 will determine the role of stromal ZC3H4 deletion in the pathologic and pathophysiologic features of BPH/LUTS in established mouse models of BPH/LUTS. Aim 3 identify the ZC3H4 cistrome and transcriptome in prostate stromal cells in response to cellular metabolic adaptations. In summary, this proposal focuses on the role of a novel regulator of genome-wide transcriptional integrity (i.e., ZC3H4) on influencing maladaptive remodeling in prostate stromal tissue that accompanies age-dependent declining mitochondrial function (i.e., particularly ETC CI).The results generated have the potential to identify new signaling pathways and molecules derived from prostate stromal cells that drive BPH/LUTS pathology and pathophysiology as well as reveal regulatory sites and non-coding transcripts that are impacted by altered mitochondrial activity.