Convergence of oncogenic and hormone receptor pathways promotes metastatic phenotypes

Abstract

Cyclin D1b is a splice variant of the cell cycle regulator cyclin D1 and is known to harbor divergent and highly oncogenic functions in human cancer. While cyclin D1b is induced during disease progression in many cancer types, the mechanisms underlying cyclin D1b function remain poorly understood. Herein, cell and human tumor xenograft models of prostate cancer were utilized to resolve the downstream pathways that are required for the protumorigenic functions of cyclin D1b. Specifically, cyclin D1b was found to modulate the expression of a large transcriptional network that cooperates with androgen receptor (AR) signaling to enhance tumor cell growth and invasive potential. Notably, cyclin D1b promoted AR-dependent activation of genes associated with metastatic phenotypes. Further exploration determined that transcriptional induction of SNAI2 (Slug) was essential for cyclin D1b-mediated proliferative and invasive properties, implicating Slug as a critical driver of disease progression. Importantly, cyclin D1b expression highly correlated with that of Slug in clinical samples of advanced disease. In vivo analyses provided strong evidence that Slug enhances both tumor growth and metastatic phenotypes. Collectively, these findings reveal the underpinning mechanisms behind the protumorigenic functions of cyclin D1b and demonstrate that the convergence of the cyclin D1b/AR and Slug pathways results in the activation of processes critical for the promotion of lethal tumor phenotypes.

Androgen receptor co-regulatory networks in castration-resistant prostate cancer

“…Notably, Slug has been well documented to be involved in the induction of epithelial-mesenchymal transition in a variety of cancers, including the prostate (Medici et al 2008, Emadi Baygi et al 2010. Indeed, Augello et al (2013) observed that knockdown of SNAI2 by siRNA significantly suppressed the invasive capacity of prostate cancer cells. In addition, this effect was more pronounced in cells that over-expressed cyclin D1b (Augello et al 2013).…”

“…To further delineate the mechanisms that underpin the pro-tumorigenic activity of cyclin D1b in prostate cancer, Augello et al (2013) carried out microarray and gene ontology analyses to identify and characterize genes uniquely regulated by cyclin D1b. They found that a number of these cyclin D1b-regulated genes are functionally associated with altered cell migration, invasion, and differentiation.…”

“…They found that a number of these cyclin D1b-regulated genes are functionally associated with altered cell migration, invasion, and differentiation. Notably, the expression of Slug (SNAI2), a member of the SNAIL family of transcriptional factors, was highly induced by cyclin D1b (Augello et al 2013). Further experiments revealed that the regulation of Slug expression was achieved through the cooperation of cyclin D1b and AR, by mediating an enrichment of acetylated histones and enhanced AR occupancy at the SNAI2 regulatory loci (Augello et al 2013).…”

“…Notably, the expression of Slug (SNAI2), a member of the SNAIL family of transcriptional factors, was highly induced by cyclin D1b (Augello et al 2013). Further experiments revealed that the regulation of Slug expression was achieved through the cooperation of cyclin D1b and AR, by mediating an enrichment of acetylated histones and enhanced AR occupancy at the SNAI2 regulatory loci (Augello et al 2013). Notably, Slug has been well documented to be involved in the induction of epithelial-mesenchymal transition in a variety of cancers, including the prostate (Medici et al 2008, Emadi Baygi et al 2010.…”

“…Indeed, Augello et al (2013) observed that knockdown of SNAI2 by siRNA significantly suppressed the invasive capacity of prostate cancer cells. In addition, this effect was more pronounced in cells that over-expressed cyclin D1b (Augello et al 2013). Taken together, these findings support that Slug is necessary and sufficient in inducing cyclin D1b-mediated pro-metastatic properties.…”