# Androgen Receptor-containing novel transcriptional complex for cancer-specific gene expression in therapy-resistant Prostate Cancer

> **NIH NIH R21** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $199,013

## Abstract

Abstract
Androgen Receptor containing novel transcriptional complex for cancer-specific gene
expression in therapy-resistant Prostate Cancer.
PI: Samikshan Dutta
Several studies indicated the importance of AR-regulated gene expression in CRPC, prompting to
the development of second-generation anti-androgen therapies such as enzalutamide and
abiraterone acetate. These drugs show limited success for treating CRPC patients because of the
emergence of several resistant mechanisms, which are either dependent or independent on AR.
One such mechanism maintains AR axis in therapy resistant-CRPC by expressing the splice
variants of AR that can function despite enzalutamide treatment. AR specific activating mutations
are also observed following abiraterone or enzalutamide treatment. To circumvent these resistant
mechanisms, a better approach would be to inhibit AR functions directly by targeting its associated
components of gene transcription. Our current study has indicated a CRPC-specific transcriptional
complex where AR is acting as a member. We observed that the nuclear localization of AR and its
splice variant is dependent on Neuropilin-2 (NRP2) in advanced PCa. NRP2 is a glycosylated,
non-kinase cell surface protein, whose expression is associated with PCa-specific death. With the
help of immunoelectron and super-resolution microscopy we observed NRP2 is present in the
nuclear membrane of CRPC cells. Further, mass spectrometry and CHIP-sequencing analysis
revealed that NRP2 helps AR and/or its splice variants to bind to the specific chromosome location
for gene transcription. We therefore hypothesized that NRP2 in the nucleus is critical for AR
driven oncogenic transcription and thus promotes aggressive CRPC. To address the
hypothesis, we will study how NRP2-AR interaction induces CRPC specific gene expression. In
support of our hypothesis, we found that NRP2 is upregulated following androgen deprivation in
PCa cells as well as during metastatic progression in human PCa tissues. We also observed that
the expression of nuclear NRP2 increases with higher Gleason pattern. Thus, depleting nuclear
NRP2 can be an effective strategy to inhibit the AR-mediated global transcriptional activation in
combination with the standard therapy. Current proposal thus implies the potential for the
development of novel therapeutic approach against metastatic and therapy-resistant PCa.

## Key facts

- **NIH application ID:** 10007772
- **Project number:** 5R21CA241234-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Samikshan Dutta
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $199,013
- **Award type:** 5
- **Project period:** 2019-09-04 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10007772

## Citation

> US National Institutes of Health, RePORTER application 10007772, Androgen Receptor-containing novel transcriptional complex for cancer-specific gene expression in therapy-resistant Prostate Cancer (5R21CA241234-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10007772. Licensed CC0.

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