ZMIZ1 Preferably Enhances the Transcriptional Activity of Androgen Receptor with Short Polyglutamine Tract

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.

Genome‐wide investigation of intragenic DNA methylation identifies ZMIZ1 gene as a prognostic marker in glioblastoma and multiple cancer types

“…The most well‐known function of ZMIZ1 is the sumoylation of androgen receptor . Additionally, ZMIZ1 interacts with the SWItch/sucrose nonfermentable nucleosome remodeling complex to possibly influence chromatin remodeling . Our in vivo findings after ZMIZ1 knockdown suggest an additional role for the gene in tumor migration.…”

A de novo t(10;19)(q22.3;q13.33) leads to ZMIZ1/PRR12 reciprocal fusion transcripts in a girl with intellectual disability and neuropsychiatric alterations

“…In line, ZMIZ1 protein interacts with BRG1 (encoded by SMARCA4) and BAF57 (encoded by SMARCE1) proteins of SWI/SNF-like BAF (BRG1/BRM-associated factors) chromatin remodeling complexes [28], among which neuron-specific complexes (nBAF) co-operate with CREST (transcriptional coactivator) in regulating the expression of genes that are essential for synaptic activity-dependent dendrite growth [29]. Moreover, ZMIZ1 can regulate FOSL1 (FRA-1) transcription [23] whose protein product is a component of AP-1 complexes that have also been related to normal synapse and dendrite growth/behavior, learning, and long-term memory [30][31][32][33].…”

Identification of a Novel Role of ZMIZ2 Protein in Regulating the Activity of the Wnt/β-Catenin Signaling Pathway

“…Both ZMIZ1 and ZMIZ2 proteins contain a strong intrinsic transactivation domain through which they augment the transcriptional activity of nuclear hormone receptors and other transcriptional factors (10,(12)(13)(14)(15)(16). We first tested the effect of ZMIZ proteins on ␤-catenin/TCF-mediated transcription.…”

“…They both contain an extended SP-RING domain, in common with other PIAS proteins (11). In addition to this domain, ZMIZ1 and ZMIZ2 proteins also contain a strong intrinsic transactivation domain through which they augment the transcriptional activity of nuclear hormone receptors and other transcription factors (10,(12)(13)(14)(15)(16)). An ortholog of ZMIZ1 and ZMIZ2, called tonalli (tna), has been identified in Drosophila and genetically interacts with the ATP-dependent SWI/SNF and Mediator complexes (11).…”