# Mechanism and role of aberrant AR activity in castration-resistant prostate cancer

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $363,713

## Abstract

PROJECT SUMMARY
Castration-resistant prostate cancer (CRPC) is the major cause of prostate cancer (PCa) mortality. Targeting
the androgens-androgen receptor (AR) axis by the second-generation endocrine therapies such as abiraterone
(ABI) and enzalutamide (ENZ) has been effective initially for CRPC treatment in clinic. However, most patients
develop resistance that undermines survival and quality of life and the therapy resistance is likely due to
expression of AR splice variants (AR-Vs) such as AR-V7 and/or other undefined mechanisms. Prostate-
specific antigen (PSA or known as KLK3) is one of the genes that are highly transcriptionally activated by AR.
Despite being extensively utilized as a biomarker for PCa diagnosis and prognosis, the significance of the PSA
gene or the entire genomic locus of this gene in PCa growth and survival has yet been well established. We
demonstrated that non-coding RNA transcribed from the PSA enhancer, or called PSA eRNA, is aberrantly
upregulated in CRPC cells in culture, xenografts and patient tissues. We further showed that expression of
PSA eRNA is regulated by AR-Vs in ENZ-resistant CRPC cells. Moreover, we showed that PSA eRNA has
cis-effects on PSA mRNA expression as well as broad trans-effects on expression of AR-regulated biologically
important genes in CRPC cells. Mechanistically, we found that PSA eRNA contains a HIV-1 TAR RNA like
(TAR-L) motif that is crucial for binding to CYCLIN T1, a key component of the positive transcription elongation
factor b (P-TEFb) complex and P-TEFb-mediated RNA polymerase II serine 2 phosphorylation (Pol II-Ser2p).
Importantly, we demonstrated that targeting PSA eRNA with generation 2.5 antisense oligonucleotides (ASOs)
inhibits growth of ENZ-resistant CRPC cells. Our further studies showed that eRNA transcribed from the FTO
gene enhancer, one of the AR-eRNAs induced by ENZ, binds to RNA splicing factors and regulates expression
of AR splice variant AR-V7 in ENZ-resistant CRPC cells. These findings support the hypothesis that aberrant
expression of AR-eRNAs including PSA and FTO eRNAs acts as a new proxy of AR functional abnormality
that promotes endocrine therapy-resistant growth of CRPC, thereby representing a novel target for CRPC
treatment. In this application, we will determine the mechanisms by which PSA eRNA regulates gene
transcription and FTO eRNA regulates AR-V7 expression in ENZ-resistant CRPC cells (Aim 1) and to
determine the functional importance and clinical significance of PSA eRNA expression in ENZ- and ABI-
resistant CRPC cells using mouse models and human patient samples (Aim 2). These studies will employ a
comprehensive approach bringing complementary expertise in tumor biology, molecular biology, medical
oncology, pathobiology, computing science and bioinformatics and biomedical statistics. Findings from the
proposed studies will significantly advance our understanding of the mechanisms that drives aberrant AR
activity and therapy-resistant growth of CR...

## Key facts

- **NIH application ID:** 9841355
- **Project number:** 5R01CA203849-03
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Haojie Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $363,713
- **Award type:** 5
- **Project period:** 2018-02-05 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841355

## Citation

> US National Institutes of Health, RePORTER application 9841355, Mechanism and role of aberrant AR activity in castration-resistant prostate cancer (5R01CA203849-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9841355. Licensed CC0.

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