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AR isoform 2 is widely expressed in human tissues and acts as a decoy receptor to regulate AR transcriptional activity

ABSTRACT: Together with the Estrogen, Progesterone, and Glucocorticoid Receptors, the Androgen Receptor (AR) is a member of the type I nuclear receptor superfamily, a class of transcription factors that are activated by steroid hormones1. Nuclear receptors share a common three-domain structure, comprising a highly variable amino-terminal domain (NTD), with potent transcriptional activator capability, a central two zinc finger motifs DNA-binding domain (DBD), and a well-conserved carboxy-terminal ligand-binding domain (LBD) responsible for interacting with the transcriptional machinery1. Given their modular structure, expression of isoforms resulting from alternative splicing or starting and termination events have profound effects on nuclear receptor activity and function. Several AR variants (AR-Vs) have been identified from prostate cancer clinical specimens, arising from multiple mechanisms, including genomic rearrangements2 and upregulation of splicing factors3. This seminal discovery has provided the molecular basis for a deeper understanding of AR-related diseases, with potential to be translated in identification of novel therapeutic targets and promising prognostic markers4–6. By deeply sequencing the transcriptome of human brains, here we identified AR-2 as the most expressed AR isoform. Furthermore, we found that AR-2 is widely expressed in other human tissues, forms heterodimers with the full length AR and acts as a repressor of its transcriptional activity. Delivery of this isoform via adeno-associated virus (AAV9) resulted in significant amelioration of the disease phenotype in a mouse model of spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease with unmet clinical need caused by a toxic gain of function of polyglutamine-expanded (polyQ) AR7. Collectively, these results establish a physiological role of AR-2 in fine-tuning full length AR activity and demonstrate the feasibility and therapeutic benefit of modulating this variant for treating SBMA and other AR-related diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE138053 | GEO | 2021/06/29

REPOSITORIES: GEO

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Project description:Reactivation of androgen receptor (AR) may drive recurrent prostate cancer in castrate patients. Ack1 tyrosine kinase is overexpressed in prostate cancer and promotes castrate resistant xenograft tumor growth and enhances androgen target gene expression and AR recruitment to enhancers. Ack1 phosphorylates AR at Tyr-267 in the N-terminal transactivation domain. In this study, the role of this phosphorylation site was investigated by characterizing the phosphorylation site mutant in the context of full length and truncated AR lacking the ligand-binding domain. The Y267F mutant showed decreased transactivation of reporters. Expression of wild type full length and truncated AR in LNCaP cells increased cell proliferation in androgen-depleted conditions and increased colony formation. However, the Y267F mutant of full length and truncated AR was defective in stimulating cell proliferation. The full length AR Y267F mutant was defective in nuclear translocation induced by androgen or Ack1 kinase. The truncated AR was constitutively localized to the nucleus. Chromatin immunoprecipitation analysis showed that it was recruited to the target enhancers without androgen. The truncated Y267F AR mutant did not exhibit constitutive nuclear localization and androgen enhancer binding activity. Expression of AR responsive genes in cells expressing truncated AR wt and AR-Y267F mutant under androgen deprived conditions was assessed by microarray gene expression analysis. The AR pathway score was increased in cells expressing truncated AR wt and decreased in cells expressing truncated AR-Y267F. These results support the concept that phosphorylation of Tyr-267 is required for AR nuclear translocation and recruitment and DNA binding and transcription of AR responsive genes. Gene expression profiling was performed using RNA samples from LNCaP cells expressing truncated AR-wt and truncated AR-Y267F growing in androgen deprived conditions. The RNA sample from vector control cells were used as reference sample. Two biological replicates were used per each cell line.

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AR isoform 2 is widely expressed in human tissues and acts as a decoy receptor to regulate AR transcriptional activity

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