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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Disrupting SUMOylation potentiates transactivation function and ameliorates polyglutamine AR-mediated disease

ABSTRACT: Our findings demonstrate beneficial effects of enhancing transactivation function of the ligand-activated polyQ AR and indicate that the SUMOylation pathway may provide new targets for therapeutic intervention. We mutated conserved lysines in the polyQ AR that are targeted by SUMO, a modification that inhibits AR transactivation function.

ORGANISM(S): Mus musculus

SUBMITTER: Richard McEachin

PROVIDER: E-GEOD-60691 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease.

Chua Jason P JP Reddy Satya L SL Yu Zhigang Z Giorgetti Elisa E Montie Heather L HL Mukherjee Sarmistha S Higgins Jake J McEachin Richard C RC Robins Diane M DM Merry Diane E DE Iñiguez-Lluhí Jorge A JA Lieberman Andrew P AP

The Journal of clinical investigation 20150120 2

Expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR) causes neuromuscular degeneration in individuals with spinobulbar muscular atrophy (SBMA). PolyQ AR has diminished transcriptional function and exhibits ligand-dependent proteotoxicity, features that have both been implicated in SBMA; however, the extent to which altered AR transcriptional function contributes to pathogenesis remains controversial. Here, we sought to dissociate effects of diminished AR function from p ...[more]

PMID: 25607844

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Disrupting SUMOylation potentiates transactivation function and ameliorates polyglutamine AR-mediated disease

Project description:Our findings demonstrate beneficial effects of enhancing transactivation function of the ligand-activated polyQ AR and indicate that the SUMOylation pathway may provide new targets for therapeutic intervention.

2015-12-21 | GSE60691 | GEO

AR function is altered by polyglutamine expansion and by SUMO

2014-08-23 | GSE50383 | GEO

A bioinformatics approach reveals novel mechanisms of the OVOL transcription factors in the regulation of epithelial-mesenchymal cell programming and cancer progression.

Project description:We find significant evidence of the OVOL, AP1, STAT1, STAT3, and NFKB1 TFs having important roles in MET. We prioritize known gene/drug targets for follow-up in the clinic, and show that the AP1/MYC TF pair is a strong candidate for intervention. Examination of the effects of OVOL1 and OVOL2 overexpression common to prostate cancer and breast cancer models.

2014-03-20 | E-GEOD-51975 | biostudies-arrayexpress

AR function is altered by polyglutamine expansion and by SUMO

Project description:Expansion of a polyglutamine (polyQ) tract in the gene for the androgen receptor (AR) results in partial loss of transactivation function and causes spinobulbar muscular atrophy (SBMA). Modification of AR by small ubiquitin-like modifier (SUMO) reduces AR function in a promoter context-dependent manner. We used microarrays to confirm and demonstrate loss of AR function from polyQ expansion and to test the degree to which AR function is altered by preventing polyQ AR SUMOylation. PC12 cells expressing AR10Q, AR112Q, or nonSUMOylatable AR112Q (KRKR) in the presence or absence of synthetic androgen R1881 were assessed for alterations in AR function by comparing gene expression changes with each AR variant in response to ligand.

2014-08-23 | E-GEOD-50383 | biostudies-arrayexpress

Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer

Project description:This paper shows, for the first time, a novel function of the OVO-like proteins (OVOL1and OVOL2) as critical inducers of mesenchymal to epithelial transition (MET) in human cancer. Examination of the effects of OVOL1 and OVOL2 overexpression in a prostate cancer model.

2013-08-01 | E-GEOD-48230 | biostudies-arrayexpress

Transcriptional profiles by deep sequencing (RNA-seq) of in vivo-generated mouse iPSCs, in vitro-generated mouse iPSCs, and mouse ESCs

Project description:We have generated M-bM-^@M-^\reprogrammableM-bM-^@M-^] transgenic mice that ubiquitously express the four Yamanaka factors in an inducible manner. Transitory induction of the transgene results in multiple teratomas emerging from a variety of organs, thus indicating that full reprogramming into iPSCs can occur in vivo. By performing bone marrow transplant experiments, we demonstrate that both hematopoietic cells, as well as non-hematopoietic cells can be reprogrammed in vivo. Remarkably, reprogrammable mice also present circulating iPSCs in the bloodstream (in vivo-iPSCs) with all the expected properties of bona fide iPSCs. Moreover, in contrast to in vitro-iPSCs or embryonic stem cells (ESCs), in vivo-iPSCs have an increased capacity to undergo trophectoderm lineage differentiation, which suggests that in vivo-iPSCs are more plastic or primitive than in vitro-generated iPSCs or ESCs. 6 clones of in vivo-generated iPSCs, 5 indendent clones of in vitro-generated iPSCs, and 3 clones of established ESCs

2013-09-12 | E-GEOD-48364 | biostudies-arrayexpress

Androgen receptor requires an optimal level of condensation to assemble androgen-induced active enhancers [GRO-Seq]

Project description:Transcription factors (TFs) activate enhancers to drive cell-specific gene expression in response to signals, but our understanding of enhancer assembly in signaling events is incomplete. Here we show that Androgen Receptor (AR), a steroid hormone signaling-regulated transcription factor, forms phase-separated condensates in response to androgen to activate enhancers. We demonstrate that the intrinsically disordered NTD of AR drives condensate formation and that NTD deletion or aromatic residue mutation reduces AR self-association and abolishes AR transcriptional activity. AR NTD can be substituted by some IDRs from other proteins for AR condensation capacity and transactivation function. Extending the polyQ tract within AR NTD strengthens AR phase separation and also leads to impaired transcriptional activity. PolyQ expansion does not affect AR binding on enhancers, but instead impairs enhancer assembly. These results suggest that AR phase separation mediates enhancer assembly, and an optimal level of AR condensation is required for its proper function in mediating AR-AR homotypic and AR-cofactor heterotypic interactions to regulate transcription in response to signals. Our study supports that alteration of the fine-tuned protein condensation might underlie AR-related human pathologies, therefore providing novel molecular insights for potential therapeutic strategies to treat prostate cancer and other AR-involved diseases by targeting AR condensation.

2023-10-31 | GSE215162 | GEO

Androgen receptor requires an optimal level of condensation to assemble androgen-induced active enhancers [ChIP-Seq]

2023-10-31 | GSE215161 | GEO

Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions

2023-10-31 | GSE215160 | GEO

ANDROGEN RECEPTOR WITH SHORT POLYGLUTAMINE TRACT PREFERABLY ENHANCES WNT/BETA-CATENIN MEDIATED PROSTATE TUMORIGENESIS

Project description:Polyglutamine (polyQ) tract polymorphism within the human androgen receptor (AR) shows population heterogeneity. African American men possess short polyQ tracts significantly more frequently than Caucasian American men. The length of polyQ tracts is inversely correlated with the risk of prostate cancer, age of onset, and aggressiveness at diagnosis. Aberrant activation of Wnt signaling also reveals frequently in advanced prostate cancer, and an enrichment of androgen and Wnt signaling activation has been observed in African American patients. Here, we investigated aberrant expression of AR bearing different polyQ tracts and stabilized β-catenin in prostate tumorigenesis using newly generated mouse models. We observed an early onset oncogenic transformation, accelerated tumor cell growth, and aggressive tumor phenotypes in the compound mice bearing short polyQ tract AR and stabilized β-catenin. RNA sequencing analysis showed a robust enrichment of Myc-regulated downstream genes in tumor samples bearing short polyQ AR versus those with longer polyQ tract AR. Upstream regulator analysis further identified Myc as the top candidate of transcriptional regulators in tumor cells from the above mouse samples with short polyQ tract AR and β-catenin. Chromatin immunoprecipitation analyses revealed increased recruitment of b-catenin and AR on the c-Myc gene regulatory locus in the tumor tissues expressing stabilized b-catenin and shorter polyQ tract AR. These data demonstrate a promotional role of aberrant activation of Wnt/b-catenin in combination with short polyQ AR expression in prostate tumorigenesis and provide mechanistic insight into aggressive prostatic tumor development that is frequently observed in African American patients.

2020-03-31 | GSE140963 | GEO

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