%0 Journal Article
%T Hedgehog in prostate cancer explained
%A Na Li
%A Ralph Buttyan
%A Shabnam Massah
%J Archive of "Oncoscience".
%D 2018
%R 10.18632/oncoscience.405
%X Hedgehog (Hh) is an oncogenic cell signaling pathway causative of skin and brain cancers [1]. While long suspected to play a role in other solid tumors, including prostate cancer, the types of mutations in upstream Hh signaling elements, especially in Patched and Smoothened (Smo), that drive hyperactive Hedgehog in skin and brain cancers are not found in these other tumors. When active, Smo suppresses a site- specific proteolysis of Gli2 and Gli3 that removes their C-terminal transactivation domains rendering them into functional repressors [2]. Smo action maintains Gli2/ Gli3 in high molecular weight, transcriptionally active forms that mediate the genomic effects of Hedgehog signaling. Recently, Li, et al [3] described a novel Smo- independent means of Gli activation in prostate cancer cells that is based upon the direct binding of androgen receptor (AR) proteins to Gli proteins. ARs (full-length liganded and constitutive-active truncated variants) recognize and bind to the C-terminal Protein Processing Domains (PPD) of Gli2 and Gli3. Furthermore it was shown that ARs effectively competed for Gli-PPD binding with the E3 ubiquitin ligase, ¦Â-TrCP, which marks Gli2/Gli3 for degradation. So AR binding to Gli2/ Gli3 effectively protects them from the constitutive degradation process that defines the Hedgehog inactive state and bypasses the need for upstream Smo activity. This identifies a new non-canonical means for Hedgehog activation in tumors and explains the failure of Smo- based therapeutics to affect progression of advanced prostate cancer [4]. More important, it shows that androgen action in prostate cancer is inexorably linked to the activity of Gli transcription factors
%K prostate cancer
%K Hedgehog
%K Androgen Receptors
%K Gli
%K Steroid Receptors
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978441/