Transcriptional Regulation in Prostate Cancer

Abstract

Prostate cancer development involves corruption of the normal prostate transcriptional network, following deregulated expression or mutation of key transcription factors. Here, we provide an overview of the transcription factors that are important in normal prostate homeostasis (NKX3-1, p63, androgen receptor [AR]), primary prostate cancer (ETS family members, c-MYC), castration-resistant prostate cancer (AR, FOXA1), and AR-independent castration-resistant neuroendocrine prostate cancer (RB1, p53, N-MYC). We use functional (in vitro and in vivo) as well as clinical data to discuss evidence that unveils their roles in the initiation and progression of prostate cancer, with an emphasis on results of chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq).

Figure 1.

Evolution of the prostate cancer network of transcription factors throughout disease progression. Normal prostate epithelium consists of basal (KRT5/14⁺) and luminal cells (KRT8/18⁺) with a transcriptional network governed by p63 or AR and NKX3-1, respectively. Prostate cancer is characterized by the expansion of AR-dependent epithelial cells harboring genetic alterations such as TMPRSS2-ERG gene fusion, c-MYC amplification, and FOXA1 mutations. The loss of the epithelial basal cell layer and the disruption of the normal tissue architecture results in the secretion of trackable levels prostate-specific antigen (PSA) into the bloodstream. The first line of androgen receptor (AR)-directed therapy results in the emergence of a castration-resistant prostate cancer (CRPC) through AR amplification, mutation, or the formation of AR messenger RNA (mRNA) splice variants (AR-Vs). Castration-resistant neuroendocrine prostate cancer (CRPC-NE) emerges following the resistance to the second generation of AR-targeted therapies. In contrast to the other stages of the disease, CRPC-NE (SYP⁺/CGA⁺/CD56⁺) is AR independent and is often driven by MYCN amplification (encoding N-MYC) and the loss of RB1 and TP53 (encoding p53) tumor-suppressing genes.