# Ecdysoneless, A Novel Regulator of Androgen Receptor

> **NIH NIH R21** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $172,293

## Abstract

PROJECT SUMMARY/ABSTRACT
 Prostate Cancer (PCa) is the most frequently diagnosed non-cutaneous cancer in men in the US and
the second most common cause of cancer deaths in men. Androgen receptor (AR) is well known driver of PCa,
and androgen deprivation therapy is the initial management, but essentially all patients eventually become
castration-resistant. Such patients are treated with next generation AR synthesis inhibitors (such as
abiraterone) or AR antagonists (such as enzalutamide) but emergence of resistance to these agents eventually
limits therapeutic choices. One of the mechanisms for such resistance is defect in AR mRNA splicing.
Expression of two splice variants AR-V1, and AR-V7 is 20-fold higher in hormone resistant PCa. The proposed
mechanisms include genomic rearrangement of the AR gene or upregulation of specific splicing factors. Two
splicing factors, pre-mRNA processing factor 8 (PRPF8) and RNA helicase DDX39B and its paralog DDX39A
seem to be involved in export and splicing of AR mRNA. Taken together a large body of evidence suggests a
role of AR processing may contribute to more aggressive PCa that is hormone resistant. Therefore, identifying
novel mechanisms those regulate AR processing is an important area of research to identify potential future
therapy targets in PCa patients.
 This R21 proposal focuses on a protein ECD, a conserved homolog of the fly Ecdysoneless gene
product, which we show is overexpressed in most PCa cell lines, and in Prostatic intraepithelial neoplasia (PIN)
and PCa tissues, and its overexpression predicts shorter survival in patients. ECD knockdown in AR+ PCa
cells reduced AR mRNA and protein levels, cell proliferation, invasion, migration and anchorage independent
growth. Mechanistically, ECD interacts with components of the R2TP co-chaperone complex that plays a key
role in the assembly of large protein or protein–RNA complexes. Importantly, the R2TP client complexes are
involved in RNA processing. We show ECD binds to PRPF8, and DDX39A and DDX39B, proteins known to
regulate mRNA export and splicing. Based on these novel findings, we hypothesize that a ternary complex of
ECD, R2TP and mRNA processing proteins (PRPF8 and DDX39) promotes AR export and splicing in PCa to
increase cell proliferation, cell survival and oncogenesis. Targeting this pathway can provide a potential PCa
therapy strategy. Here, we will first define the composition of the ECD-containing mRNA processing machinery
complexes in PCa cells using biochemical and co-localization approaches. Then we will assess the role of
ECD in recruiting the mRNA processing machinery to regulate AR mRNA export and splicing in PCa cells.
Finally, we will assess the potential of targeting AR mRNA processing by ECD knockdown or by use of CK2
inhibitor with or without enzalutamide. Thus, our studies will establish a new mechanistic paradigm of how PCa
hyper-proliferation, cell survival and hormone resistance is driven by a novel mechanism and targeting ...

## Key facts

- **NIH application ID:** 9949680
- **Project number:** 5R21CA241055-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** VIMLA BAND
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $172,293
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949680

## Citation

> US National Institutes of Health, RePORTER application 9949680, Ecdysoneless, A Novel Regulator of Androgen Receptor (5R21CA241055-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9949680. Licensed CC0.

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