CREB5 regulates stem cell-like transcriptional programs to enhance tumor progression in prostate cancer

Abstract

Prostate gland cells can be transcriptionally and morphologically characterized as basal and luminal. About 30–40% of advanced prostate cancers (PC) harbor basal-like transcription programs. In castration-resistant PC (CRPC), studies indicate that basal and stem cell-like (SCL) tumors are major resistance mechanisms to androgen receptor (AR)-targeted therapies. SCL tumors have reduced AR activity and increased stem-cell activity that promotes tumor formation, which contributes to poor clinical outcomes. We determined that CREB5 is a key regulator of basal and SCL transcriptional programs and tumor-forming phenotypes in PC. Through in silico modeling of PC transcriptomes and several pre-defined PC signaling programs, CREB5 expression was best associated with basal-like gene signatures and SCL-associated genes in primary PC and CRPCs (n = 493 and 208). This included associations with FOSL1 and other AP-1 transcription factors. We further found that CREB5 interacted with AP-1 proteins and bound to the regulatory elements of AP-1 genes, suggesting a mechanistic role in regulating the activity of AP-1 genes. In AR-positive cells, CREB5 overexpression promoted cell colony growth with tumorigenic properties and increased tumor size in vivo. These findings implicate CREB5 as a driver of the transcriptional programs underlying AR-independent basal and SCL CRPC subtypes, and this activity is detectable in primary PC.