# Dissecting the role of UBE2J1 in prostate cancer

> **NIH NIH F31** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $38,017

## Abstract

PROJECT SUMMARY
 Prostate cancer (PCa) is the most diagnosed cancer among American men and many patients with
primary PCa will eventually develop metastatic disease. Metastatic disease is often resistant to the current
“standard-of-care” treatment, androgen receptor (AR) targeted therapies, such as enzalutamide. Resistance to
AR targeted therapies largely limits the clinical outcome of patients with advanced PCa. Therefore, there is an
unmet need for revealing the molecular mechanisms of resistance and identifying novel vulnerabilities to
overcome it. Through a comprehensive in vivo library screen, we have identified Ubiquitin Conjugating Enzyme
E2 J1 (UBE2J1), which is lost in 8-15% of patients with PCa, as one of the top candidate modifiers of response
to AR targeted therapy. Through CRISPR-mediated knock-out, I demonstrated that UBE2J1 depletion in
LNCaP/AR PCa cells confers resistance to AR targeted therapies. Furthermore, UBE2J1 depletion also confers
resistance to Androgen Deprivation Therapy (ADT). Mechanistically, I have observed significantly increased
expression of AR and AR target genes in cells with UBE2J1 depletion, suggesting the loss of UBE2J1 may slow
down the ubiquitin mediated degradation of AR. This hypothesis is further supported by the observation of a
significant increase of AR binding in AR regulated enhancer sites upon UBE2J1 depletion. Strikingly, restoring
AR degradation in UBE2J1 deleted cells with two innovative AR PROTACs rescues the sensitivity to ADT.
Furthermore, as UBE2J1-loss promotes ER associated degradation pathway (ERAD), it might rescue cell death
caused by a ER stress inducing microenvironment including therapy treatment. I have observed a significant
increase of key ER-stress regulator, GRP78. Collectively, my preliminary data suggests the loss of UBE2J1
may confer AR targeted therapy resistance through impaired AR degradation and promoting ERAD and
rescuing tumor cell apoptosis caused by AR targeted therapy. I propose two specific aims to examine this
hypothesis and elucidate the function and molecular mechanism of UBE2J1-loss conferred resistance to AR
therapy. For the first aim, I will comprehensively elucidate the consequence of UBE2J1 depletion both in vitro
and in vivo, using other PCa cell lines and SCID mouse xenograft models. For the second aim, I will reveal the
mechanism by which UBE2J1 causes AR-targeted therapy resistance. I will explore whether UBE2J1, as an E2
ubiquitin conjugating enzyme, targets AR for degradation and regulates AR signaling. On the other hand, I will
examine ERAD and ER stress in cells with UBE2J1 depletion and determine whether rescuing cell death is the
mechanism of resistance to AR targeted therapy. The successful completion of this study will contribute novel
insights into the mechanism of resistance to AR targeted therapies, advancing our understanding of the
connection between AR degradation and ERAD to therapy resistance. It may also lead to the identification of
ne...

## Key facts

- **NIH application ID:** 10386745
- **Project number:** 1F31CA261019-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Carla Sofia Rodriguez-Tirado
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $38,017
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10386745

## Citation

> US National Institutes of Health, RePORTER application 10386745, Dissecting the role of UBE2J1 in prostate cancer (1F31CA261019-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10386745. Licensed CC0.

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