African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome...

Area of Science:

• Genomics
• Molecular Biology
• Cancer Research

Background:

• African American (AA) men have a higher incidence of prostate cancer and vitamin D deficiency.
• The role of the vitamin D receptor (VDR) in prostate cancer genomic regulation among different ancestral groups is not well understood.

Purpose of the Study:

• To investigate VDR proteogenomic actions in European American (EA) and AA prostate cancer.
• To identify genomic factors contributing to VDR dysfunction in AA prostate cancer.

Main Methods:

• Proteogenomic analyses using Rapid Immunoprecipitation Mass Spectrometry of Endogenous Protein (RIME).
• Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) and Chromatin Immunoprecipitation sequencing (ChIP-seq).
• RNA sequencing and analysis of clinical prostate cancer cohorts.

Main Results:

• AA prostate cells exhibit greater VDR complex dynamism and 1α,25(OH)2D3-regulated gene expression compared to European American (EA) cells.
• Reduced expression of the chromatin remodeler BAZ1A was observed in AA prostate cancer and correlated with impaired VDR function.
• VDR-associated genomic features predicted prostate cancer progression and treatment response specifically in AA patients.

Conclusions:

• Genomic ancestry significantly influences VDR complex composition, genomic distribution, and transcriptional function.
• BAZ1A plays a critical role in VDR transcriptional control, and its disruption is a novel driver in AA prostate cancer.
• Targeting BAZ1A-VDR interactions may offer a new therapeutic strategy for AA prostate cancer.