Abstract 3390: Epigenetic corruption of the Vitamin D signaling in prostate cancer

Abstract

Abstract Prostate epithelial cells are sensitive to nuclear receptor (NR) ligands, activating downstream targets and reducing proliferation rate. However, advanced prostate cancer (PCa) cells lose their sensitivity to NR ligands such as the secosteroid hormone 1,25(OH)2D3 (VitD). The Lysine Specific Demethylase 1A (LSD1) belongs to the nucleosome remodeling and deacetylase (NuRD) complex and targets lysine residues on histone and non-histone proteins. LSD1 is upregulated in PCa tumors and binds to the VitD Receptor (VDR), modulating VDR target gene transcription. LSD1 knockdown increases cells sensitivity to VitD while increasing basal proliferation rate. LSD1 overexpression further increases PCa cells sensitivity to VitD leading to a significant reduction in cell viability. Transcriptionally, LSD1 acts as both coactivator and corepressor for transcription factors, including the Androgen Receptor (AR) and VDR. Upon treatment with VitD, LSD1 mediates VDR-dependent transcription by repressing Cdkn1a and E2f1 VDR induced transcription and promoting Cyp24a1 and S100g mRNA accumulation. Furthermore LSD1 knockdown leads to a reduction of Cdkn1a basal expression. VitD treatment also promotes the physical association of LSD1 with nuclear HDAC2 and VDR. ChIP analysis in cells with reduced LSD1 levels showed differential recruitment of VDR, DNMT1 and phospho-PolII and differential histone modification (acetylation and methylation) levels at the TSS region of the genes analyzed upon VitD treatment. Significantly different recruitment of the previously mentioned proteins is also observed at the TSS region of untreated cells, suggesting that LSD1 modulates chromatin structure and transcription factor recruitment independently from VDR status. MassARRAY Quantitative DNA Methylation Analysis and microfluidic methylation array experiments investigated the methylation status of VDR target genes and PCa relevant genes. Analysis of TCGA clinical samples using LSD1 and DNMT1 as beacon revealed a gene signature altered in 40-90% of the data, enriched in networks involved in cell cycle control, chromatin modification and transcriptional regulation. VDR-mediated transcription in advanced PCa is squelched by differential activity of coregulatory proteins. LSD1 is overexpressed in malignancies and suggested as therapeutic target. Furthermore, NR ligands are currently used in clinical trials to test their chemotherapeutic/chemopreventive effect. This newly identified role for LSD1 in the VDR transcriptional network will help better defining the mechanism or resistance of advanced PCa to NR ligands. Citation Format: Sebastiano Battaglia, Steven Seedhouse, Ellen Karasik, Dominic Smiraglia, Barbara Foster. Epigenetic corruption of the Vitamin D signaling in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3390. doi:10.1158/1538-7445.AM2014-3390