Abstract The Ubiquitin-specific protease 21 (USP21) is a deubiquitinase with pro-carcinogenic effects in various cancers. While its role and molecular mechanism in prostate cancer remain elusive. To investigate the role of USP21 in promoting prostate cancer, we evaluated that USP21 shows the highest mRNA expression in prostate cancer patients, and high USP21 levels predicted a poor prognosis in patients with prostate cancer. Additionally, suppression of USP21 significantly inhibited prostate cancer cell proliferation. In vivo, USP21 depletion significantly suppressed tumor growth in xenograft models. Moreover, we identified the androgen receptor (AR) as a potential substrate of USP21 by tandem affinity purification. Mechanistically, i) USP21 directly interacted and stabilized AR by deubiquitinating its K48-linked polyubiquitination, which is a main driver for prostate cancer. Silencing of USP21 enhances polyubiquitination of AR, promotes its proteasomal degradation, and ultimately attenuates PSA, while these effects could be largely restored by reintroduction of AR. ii) USP21 regulates transcriptional activity of AR according to our RNA-seq studies, we revealed that siUSP21 decreases both androgen response and AR-induced pathways, and knockdown USP21 decreases mRNA level of AR target genes. In conclusion, our project gives insight into the mechanism underlying how USP21 regulates AR to promote the progression of prostate cancer , therefore providing a novel approach for prostate cancer treatment. Citation Format: Cheng Zhang, . The role of USP21 in prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7359.
Cheng Zhang (Fri,) studied this question.