Abstract
The androgen receptor (AR) is a ligand-induced transcription factor and contains the polyglutamine (polyQ) tracts within its N-terminal transactivation domain. The length of polyQ tracts has been suggested to alter AR transcriptional activity in prostate cancer along with other endocrine and neurologic disorders. Here, we assessed the role of ZMIZ1, an AR co-activator, in regulating the activity of the AR with different lengths of polyQ tracts as ARQ9, ARQ24, and ARQ35 in prostate cancer cells. ZMIZ1, but not ZMIZ2 or ARA70, preferably augments ARQ9 induced androgen-dependent transcription on three different androgen-inducible promoter/reporter vectors. A strong protein-protein interaction between ZMIZ1 and ARQ9 proteins was shown by immunoprecipitation assays. In the presence of ZMIZ1, the N and C-terminal interaction of the ARQ9 was more pronounced than ARQ24 and ARQ35. Both Brg1 and BAF57, the components of SWI/SNF complexes, were shown to be involved in the enhancement of ZMIZ1 on AR activity. Using the chromatin immunoprecipitation assays (ChIP), we further demonstrated a strong recruitment of ZMIZ1 by ARQ9 on the promoter of the prostate specific antigen (PSA) gene. These results demonstrate a novel regulatory role of ZMIZ1 in modulating the polyQ tract length of AR in prostate cancer cells.
Highlights
Androgen signaling is mainly mediated through the androgen receptor (AR) and plays a critical role in male sexual development and in normal and malignant prostatic cell growth and survival [1]
Expression vectors for the human AR cDNA containing 9, 24, and 35 polyQ tracts and for AR cofactors, including ZMIZ1, ZMIZ2, and ARA70, were co-transfected with an androgen-induced luciferase reporter driven by a 7 Kb prostate specific antigen (PSA) promoter-enhancer fragment into prostate cancer cell line, DU145
It has been shown that the intramolecular interaction between the AR N-terminal transactivation domain (NTD) and ligand-binding domain (LBD) is essential for forming a composite binding site to recruit transcriptional co-regulators to confer the full transcriptional activity [41]
Summary
Androgen signaling is mainly mediated through the androgen receptor (AR) and plays a critical role in male sexual development and in normal and malignant prostatic cell growth and survival [1]. Expansion of the polyQ length within the AR NTD directly links to spinal and bulbar muscular atrophy/Kennedy’s disease (SBMA), a rare, X-linked, adult onset, neurodegenerative disorder [3,4,5]. Male patients with this disorder often have symptoms of partial androgen insensitivity indicative of aberrant AR function, such as gynecomastia and testicular atrophy [6,7]. Multiple lines of evidence have shown that the length of the AR polyQ tract is inversely correlated with the risk of developing prostate cancer, age of onset, and risk of advanced disease at diagnosis [10,11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
