A positive role of c-Myc in regulating androgen receptor and its splice variants in prostate cancer

Abstract

Increased expression of the full-length androgen receptor (AR-FL) and AR splice variants (AR-Vs) drives the progression of castration-resistant prostate cancer (CRPC). The levels of AR-FL and AR-V transcripts are often tightly correlated in individual CRPC samples, yet our understanding of how their expression is co-regulated is limited. Here, we report a role of c-Myc in accounting for coordinated AR-FL and AR-V expression. Analysis of gene expression data from 159 metastatic CRPC samples and 2142 primary prostate tumors showed that the level of c-Myc is positively correlated with that of individual AR isoforms. A striking positive correlation also exists between the activity of the c-Myc pathway and the level of individual AR isoforms, between the level of c-Myc and the activity of the AR pathway, and between the activities of the two pathways. Moreover, the c-Myc signature is highly enriched in tumors expressing high levels of AR, as is the AR signature in c-Myc-high-expressing tumors. Using shRNA knockdown, we confirmed c-Myc regulation of expression and activity of AR-FL and AR-Vs in cell models and a patient-derived xenograft model. Mechanistically, c-Myc promotes the transcription of the AR gene and enhances the stability of the AR-FL and AR-V proteins without altering AR RNA splicing. Importantly, inhibiting c-Myc sensitizes enzalutamide-resistant cells to growth inhibition by enzalutamide. Overall, this study highlights a critical role of c-Myc in regulating the coordinated expression of AR-FL and AR-Vs that is commonly observed in CRPC and suggests the utility of targeting c-Myc as an adjuvant to AR-directed therapy.

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

“…Based on these prior findings, as HOXB13 physically interacts with MEIS1 [18], tumors expressing less MEIS1 would be expected to display 21 greater HOXB13 expression and AR activity. Indeed, we show an inverse relationship between MEIS1 expression and AR activity in two independent cohorts, which is consistent with previous observations of a positive correlation between MYC expression and AR activity [7].…”

“…These include down-regulation of the tumor suppressors NKX3-1 and PTEN (often due to genomic deletion), up-regulation of ERG (due to fusion with TMPRSS2), and up-regulation of MYC, which often co-occurs with a single-copy gain of chromosome 8q24 [1][2][3][4][5]. 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].…”

“…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].…”

Role of CYP3A5 in Modulating Androgen Receptor Signaling and Its Relevance to African American Men with Prostate Cancer

“…c-MYC induces AR gene transcription and is frequently upregulated in CRPC. A positive correlation between c-MYC and AR mRNA has been reported [32][33][34][35][36]. ELL2 (elongation factor, RNA polymerase II) is encoded by an androgen-response gene in the prostate [30,37]; it suppresses transient pausing of RNA polymerase II activity along the DNA strand and facilitates the transcription process [38].…”

Long Non­coding RNA SNHG16 Functions as Tumor Activator by Sponging hsa-miR-373-3p to Regulate TGFBR2/SMAD Pathway in Prostate Cancer

“…The c-MYC is a proto-oncogene and plays a role in cell cycle progression, apoptosis and cellular transformation. The high expression of c-MYC could promote the development of PCa by the transcription of the androgen receptor gene and enhance the stability of the full-length androgen receptor and androgen receptor splice variants proteins [23]. E2F4 were overexpressed in PCa epithelial cells [24], and regulated cell cycle by forming complexes with P130 [25].…”