The Androgen Receptor Bridges Stem Cell-Associated Signaling Nodes in Prostate Stem Cells

Abstract

The therapeutic potential of stem cells relies on dissecting the complex signaling networks that are thought to regulate their pluripotency and self-renewal. Until recently, attention has focused almost exclusively on a small set of "core" transcription factors for maintaining the stem cell state. It is now clear that stem cell regulatory networks are far more complex. In this review, we examine the role of the androgen receptor (AR) in coordinating interactions between signaling nodes that govern the balance of cell fate decisions in prostate stem cells.

Figure 1

Regulation of interconnected stem cell signaling nodes by the AR. Activation of the AR negatively regulates the core pluripotency transcription factors (Nanog, Sox2, and Oct4) as well as signaling cascades that reinforce a robust stem cell state. The AR (1) acts as a transcriptional repressor at the Nanog and Sox2 promoters; (2) inhibits PI3K/Akt signaling through induction of PHLPP, which dephosphorylates Akt to facilitate ERK pathway activation leading to Nanog gene repression, as well as GSK3-mediated c-myc and β-catenin repression; and (3) blocks STAT3-mediated transcription of stem cell-associated genes by inhibiting IL-6. Suppression of the AR by factors in the stem cell niche, such as CCL5, relieves this inhibition to favor self-renewal and pluripotency over differentiation. AR, androgen receptor; β-CAT, β-catenin; CCL5, chemokine ligand 5; IL-6, interleukin-6; JAK, Janus kinase; PHLPP, PH domain and leucine rich protein phosphatase; RTK, receptor tyrosine kinase.