The Sex-determining region Y-box 4 and homeobox C6 transcriptional networks in prostate cancer progression: crosstalk with the Wnt, Notch, and PI3K pathways

Abstract

The transforming growth factor beta, Hedgehog, Notch, and Wnt signaling pathways all play critical roles in the development and progression of prostate cancer. It is becoming increasingly apparent that these pathways may intersect with developmentally important transcription factors such as the sex-determining region Y-box 4 (SOX4), homeobox C6, enhancer of zeste 2, and ETS-related gene, which are up-regulated in prostate cancers. For example, identification of the downstream targets of SOX4 and homeobox C6 suggests that these factors may cooperate to activate the Notch pathway and the PI3K/AKT pathway, possibly in response to Wnt signals. PI3K/AKT activation likely occurs indirectly via up-regulation of growth factor receptors, while Notch activation is secondary to up-regulation of Notch pathway components. In addition, SOX4 may affect terminal differentiation via regulation of other transcription factors such as NKX3.1 and MLL, and regulation of components of the microRNA pathway such as Dicer and Argonaute 1. The evidence supporting activation of these pathways in prostate cancer progression suggests that combinations of compounds targeting them may be of benefit to patients with aggressive, metastatic disease.

Figure 1

Schematic of the Notch pathway. The Notch receptor is synthesized in the rough endoplasmic reticulum as a single polypeptide precursor and proteolytically cleaved in the trans-golgi network by the furin protease, creating a heterodimeric mature receptor that comprises noncovalently associated extracellular and transmembrane subunits. This assembly travels to the cell surface where it interacts with specific transmembrane ligands, such as jagged and δ-like 1. Notch activation can be repressed by BMP7 via an unknown mechanism. Following ligand activation and further proteolytic cleavage by ADAM10 and presenilin-1 (PSEN1) proteases, the Notch intracellular domain (NICD) is released and translocates to the nucleus where it regulates gene expression, converting CSL (C-promoter binding factor (CBF-1), suppressor of hairless (Su(H)), lin-12 and glp-1 (Lag-1)) repressor complexes into activator complexes, and inducing expression of the hairy-enhancer of split genes (eg, HES2 and HEY1).

Figure 2

Model of the effects of the SOX4 and HOXC6 transcriptional networks on PI3K-AKT pathway activation in prostate cancer. Genes up-regulated by SOX4 or HOXC6 are shown in red, and repression targets are shown in green. Yellow indicates activation.

Figure 3

Model of the effects of SOX4 and HOXC6 on Notch pathway activation and metastasis. Genes up-regulated by SOX4 or HOXC6 are shown in red, and repression targets are shown in green. Yellow indicates activation. PSEN1 = presenilin-1; TNC = tenascin C.

Figure 4

Immunohistochemistry of formalin-fixed, paraffin-embedded prostate adenocarcinomas with affinity-purified SOX4 antibodies. SOX4 detection is dark brown; nuclei were counterstained with hematoxylin (blue). Prostate cancer (asterisks) stains much more intensely than benign epithelium (arrowheads). Note the dark staining of some nuclei, consistent with a role of SOX4 in transcription. Negative controls without primary antibody showed no staining of any cell type (not shown). Original magnification: ×400 (A and B); ×600 (C and D).