Text · study · 2026
An androgen receptor pre-mRNA stem loop structure determines splicing fate of AR-V7 in prostate cancer
Listed in NCBI GEO
In castration-resistant prostate cancer (CRPC), detection of androgen receptor (AR) splice isoform AR-V7 correlates strongly with resistance to AR pathway inhibitors (ARPI) and poor patient outcomes.
Description
AR-V7 incorporates transcript-terminating cryptic exon 3 (CE3), which excludes the ligand binding domain from the AR protein, thereby enabling AR-driven transcriptional regulation independent of androgens. While several CE3 splicing regulatory proteins have been described, the impact of pre-mRNA structures in this region is unknown.
We performed SHAPE-MaP to develop the first experimentally informed secondary structure model of the CE3 3' splice site. This model predicted a previously undescribed RNA stem loop structure, which we hypothesized could inhibit AR-V7 biogenesis. Using an AR-V7 minigene assay, we observed decreased AR-V7 abundance in response to stabilization of this structure, leading us to term it the cryptic exon 3-splicing inhibitory stem loop (CE3-SISL). ∆SHAPE analysis supported a protein interaction at this site that is lost in androgen independence.
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Using quantitative proteomics, we nominated candidate interactors, such as neuro-oncological ventral antigen 1 (NOVA1), that may help explain the repressive function of CE3-SISL. Together, these data support the importance of this RNA structure in AR-V7 biogenesis and suggest a potential target for AR-V7-depleting agents. As a proof of concept, we developed several CE3-SISL-targeting antisense oligonucleotides (ASOs), which showed almost complete inhibition of AR-V7 biogenesis in both the minigene assay and in endogenous AR-V7-expressing cells with or without the ARPI enzalutamide.
CE3-SISL is therefore functional in AR-V7 biogenesis and can serve as a structural target in therapeutic development for AR-V7-driven CRPC.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE307nnn/GSE307202 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE307202 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1314747 ncbi.nlm.nih.gov/bioproject/PRJNA1314747 ↗
project · from NCBI GEO
Topics
- Stated by source
- Homo sapiens · Other
- From keywords
- Life Sciences
- Inferred from text
- Cancer 75% · Mass spectrometry 65%
Provenance · 1 source records, 9 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE307202 | 13 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:cancer | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:other | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:mass-spectrometry | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (65%) |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |