The hedgehog/Gli signaling paradigm in prostate cancer

Abstract

Hedgehog is a ligand-activated signaling pathway that regulates Gli-mediated transcription. Although most noted for its role as an embryonic morphogen, hyperactive hedgehog also causes human skin and brain malignancies. The hedgehog-related gene anomalies found in these tumors are rarely found in prostate cancer. Yet surveys of human prostate tumors show concordance of high expression of hedgehog ligands and Gli2 that correlate with the potential for metastasis and therapy-resistant behavior. Likewise, prostate cancer cell lines express hedgehog target genes, and their growth and survival is affected by hedgehog/Gli inhibitors. To date, the preponderance of data supports the idea that prostate tumors benefit from a paracrine hedgehog microenvironment similar to the developing prostate. Uncertainty remains as to whether hedgehog’s influence in prostate cancer also includes aspects of tumor cell autocrine-like signaling. The recent findings that Gli proteins interact with the androgen receptor and affect its transcriptional output have helped to identify a novel pathway through which hedgehog/Gli might affect prostate tumor behavior and raises questions as to whether hedgehog signaling in prostate cancer cells is suitably measured by the expression of Gli target genes alone.

Keywords::

• androgen signaling
• cyclopamine
• Gli
• hedgehog signaling
• prostate cancer
• Smoothened

Financial & competing interests disclosure

Mengqian Chen is supported by a training grant from the United States Department of Defense Prostate Cancer Research Program (W81XH-10-1-0125). Ralph Buttyan is supported from grants from the NIH (RO1-CA11618) and from the United States Department of Defense Prostate Cancer Research Program (W81XH-10-1-0493 and W81XH-06-0061). The authors have no other relevant affiliations or financial involvements with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.