# Unveiling the Role of UBE2J1 as the E2 Ubiquitin Conjugating Enzyme in Androgen Receptor Degradation

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $399,714

## Abstract

PROJECT SUMMARY Overall research plans/aims have NOT changed.
Despite the significant clinical success of AR-targeted therapies in the management of prostate cancer (PCa),
resistance to these treatments remains a significant challenge. This resistance often manifests as persistent or
even elevated levels of AR and AR signaling. Emerging evidence indicates that the dysregulation of the
ubiquitination-based protein degradation process is pivotal in the accumulation of oncogenic proteins like AR,
contributing to therapeutic resistance. While the role of various E3 ligases in the degradation of AR and the
tumorigenesis of PCa has been extensively studied, there is a crucial yet unaddressed gap in our understanding
regarding the specific E2 enzyme responsible for AR degradation. Our research identifies UBE2J1 as the
authentic E2 ubiquitin conjugating enzyme accountable for AR ubiquitination in PCa. Preliminary results reveal
that the frequent loss of UBE2J1 in 10-15% of PCa patients leads to dysregulated AR ubiquitination and
degradation, contributing to its accumulation and resistance to AR-targeted therapy. By utilizing ubiquitination-
based AR degraders, we have successfully reinstated AR degradation and impeded the growth of therapy-
resistant PCa tumors. In light of these compelling findings, we propose three aims to validate the central
hypothesis that UBE2J1 serves as the E2 ubiquitin conjugating enzyme in regulating AR degradation and
resistance to AR-targeted therapies. The overarching goal of this study is to unravel the molecular functions
of UBE2J1 in governing AR ubiquitination, degradation, and various facets of PCa tumorigenesis and therapy
resistance. In Aim 1, we will undertake a comprehensive analysis of the role of UBE2J1 in regulating AR functions
across multiple stages of PCa, employing both in vitro and in vivo models. We will utilize single-cell RNA
sequencing and spatial transcriptomics to assess the effect of UBE2J1-loss on tumor heterogeneity and
resistance at single-cell resolution. In Aim 2, we will comprehensively dissect the molecular mechanisms through
which UBE2J1 regulates AR degradation. We will identify the critical domains of UBE2J1, pinpoint the specific
interaction and ubiquitination sites on AR, and reveal the E3 ligase responsible for UBE2J1-mediated AR
degradation. We will also explore alterations in the AR cistrome and transcriptome landscape in the context of
UBE2J1-loss. In Aim 3, we will initially evaluate the in vitro and in vivo effectiveness of restoring AR degradation
using PROTAC-based AR degraders AC67 and AC176 in various UBE2J1-KO PCa models. We will
subsequently assess the predictive value of UBE2J1 expression as a biomarker for responses to both AR
antagonists and AR degraders. Completion of this project will not only substantially refine our comprehension of
the molecular mechanisms governing AR degradation and therapy resistance in advanced PCa but pave the
way for the development of an impactfu...

## Key facts

- **NIH application ID:** 11235246
- **Project number:** 7R01CA292949-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Ping Mu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $399,714
- **Award type:** 7
- **Project period:** 2024-07-15 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11235246

## Citation

> US National Institutes of Health, RePORTER application 11235246, Unveiling the Role of UBE2J1 as the E2 Ubiquitin Conjugating Enzyme in Androgen Receptor Degradation (7R01CA292949-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11235246. Licensed CC0.

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