Epigenetic Aging in TMPRSS2 Fusion-Negative African American Prostate Cancer
Abstract
There is strong evidence that altered signaling via the vitamin D receptor (VDR) makes a significant contribution to AA PCa in the absence of the oncogenic actions of TMPRSS2:ERG fusion events. We have now undertaken the first integrative genomic analyses of the VDR cistrome-transcriptome in the context of health disparities using EA and AA cell models. These analyses lend strong evidence to the concept that the VDR is a significantly more potent transcriptional regulator in non-malignant AA prostate epithelial cells than EA cells, and that altered expression of the BAZ1A/SMARCA5 chromatin remodeling complex distorts VDR actions. We therefore propose to study how alteredBAZ1A/SMARCA5-VDR interactions impact the circadian rhythm and lead to increased epigenetic aging in AA TMPRSS2 fusion negative PCa. We hypothesize that TMPRSS2 fusion negative PCa arises more frequently in AA men due to altered VDR transcriptional control of protein coding and non-protein coding genes that are significantly enriched for anti-inflammatory and circadian rhythm pathways. Disrupted VDR signaling arises through two mechanisms, i. reduced expression of the BAZ1A/SMARCA5 chromatin remodeling complex, and ii. Elevated miRNA expression targeting the same networks. The combined impact directly and indirectly lead to changes in CpG methylation at sites that are important for the control of epigenetic aging.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2023
- Accession Number
- AD1219935
Entities
People
- Christopher C Coss
Organizations
- Ohio State University