c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks

Abstract

Prostate cancer (PCa) is the most common non-cutaneous cancer in men. The androgen receptor (AR), a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signaling networks have been shown to be altered in patients and to influence AR activity. Amongst these, the oncogenic transcription factor c-Myc has been studied extensively in multiple malignancies and elevated protein levels of c-Myc are commonly observed in PCa. Its impact on AR activity, however, remains elusive. In this study, we assessed the impact of c-Myc overexpression on AR activity and transcriptional output in a PCa cell line model and validated the antagonistic effect of c-MYC on AR-targets in patient samples. We found that c-Myc overexpression partially reprogrammed AR chromatin occupancy and was associated with altered histone marks distribution, most notably H3K4me1 and H3K27me3. We found c-Myc and the AR co-occupy a substantial number of binding sites and these exhibited enhancer-like characteristics. Interestingly, c-Myc overexpression antagonised clinically relevant AR target genes. Therefore, as an example, we validated the antagonistic relationship between c-Myc and two AR target genes, KLK3 (alias PSA, prostate specific antigen), and Glycine N-Methyltransferase (GNMT), in patient samples. Our findings provide unbiased evidence that MYC overexpression deregulates the AR transcriptional program, which is thought to be a driving force in PCa.

Concise Review: Prostate Cancer Stem Cells: Current Understanding

“…Of interest, overexpression of MYC antagonizes the AR-dependent transcription program and confers the growth advantage in tumor cells in the absence of androgens. Therefore, increase in MYC expression may promote androgen-independent prostate tumor progression [65,89].…”

The Pioneering Role of GATA2 in Androgen Receptor Variant Regulation Is Controlled by Bromodomain and Extraterminal Proteins in Castrate-Resistant Prostate Cancer

“…Further interrogation of our CWR22Rv1-derived transcriptomic data also provided evidence that GATA2 regulates the activity of other oncogenic transcription factors, including c-Myc and E2F1. This was confirmed in silico using transcriptomic and cistromic data sets derived from LNCaP cells (30,34), which indicated considerable DNA-binding site and target gene overlaps between GATA2 and both c-Myc and E2F1. Consistent with GATA2 regulating the transcriptional competency of AR-Vs and other key CRPC-associated transcription factors, depletion of GATA2 markedly reduced expression of genes involved in the cell cycle and attenuated proliferation of CWR22Rv1 cells.…”

“…Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8 was also used to identify pathways affected by GATA2 depletion. The GATA2-LNCaP gene signature was a kind gift from Nicholas Mitsiades (26), the c-Myc gene signature was downloaded from Barfeld and colleagues (30), and the 0.5 mmol/L I-BET762 LNCaP gene signature was downloaded from Wyce and colleagues (31).…”

“…ChIP-Seq data are publicly accessible with the accession number GSE125236. Fastq files for BRD2, BRD3, BRD4, and AR À/þ DHT were downloaded from Asangani and colleagues (14), c-Myc and E2F1 fastq files were downloaded online from Barfeld and colleagues (30) and Xu and colleagues (34), respectively, and the LNCaP GATA2 BED file was a kind gift from Nicholas Mitsiades (26). The raw read data were aligned to the human genome hg38 assembly using Bowtie2 with default parameters.…”

MEIS1 down-regulation by MYC mediates prostate cancer development through elevated HOXB13 expression and AR activity

“…Interestingly, up-regulation of MYC in most neoplastic tissues is a very early event that contributes to self-renewal and proliferation, but localized prostate cancer (PCa) is not hyperproliferative and focal amplification of MYC is rare [6,7]. In part, the effects of the androgen receptor (AR) in terminally-differentiated luminal prostate cells are disrupted by MYC and other cofactors including FOXA1 and HOXB13 to re-engage proliferative processes during tumorigenesis [7][8][9][10][11].…”