Emily Hong

Background: Castration-resistant prostate cancer (CRPC) is late-stage prostate cancer.⁸ Prostate cancer, the second-most common malignancy for men, needs androgens for progression and growth at early stages.⁷ Despite 80-90% therapeutic efficiency of androgen deprivation therapy (ADT), 10-20% of prostate cancer cases become resistant to ADT and progress to CRPC within 2-3 years.¹ Enzalutamide, an androgen receptor (AR) inhibitor, is a first-line treatment of CRPC and improves 5-year survival rate, progression-free survival, and overall survival.^13,8 CRPC frequently develops resistance to Enzalutamide, and restoring sensitivity to Enzalutamide is crucial to improve CRPC treatment.⁸ 18.3% of high-risk CRPC patients carry AR-V7 (androgen receptor variant 7) that is normally degraded by the ubiquitin-proteasome pathway, but protected by USP-AR/AR-V7 complexes through AR deubiquitination.^13,1 Therefore, research has been conducted on targeting pathways that promote AR deubiquitination to restore CRPC sensitivity to Enzalutamide.¹

Objective: We aim to summarize effects and mechanisms of promoting AR/AR-V7 deubiquitination on CRPC sensitivity to Enzalutamide.

Search Methods: An online search in PubMed database was conducted (2018 to 2023), using keywords: “castration-resistant prostate cancer,” “Enzalutamide resistance,” “AR-V7,” and “ubiquitination.”

Results: PCBP1-AS1 is a long non-coding RNA (lnc) that stabilizes the binding of AR/AR-V7 with Ubiquitin specific peptidase 22 (USP22), thus allowing for AR and AR-V7 deubiquitination.¹ Lnc-PCBP1-AS1 depletion restored sensitivity of CRPC cells to Enzalutamide with less USP-AR/AR-V7 complex stabilization.¹ Treating CRPC cells with PCBP1-AS1 depletion sequence before implantation into mice led to decreased tumor volume and growth.¹ Kinesin family member 15 (KIF15) plays critical roles in proliferation, apoptosis, and differentiation, and is upregulated in Enzalutamide-resistant CRPC cells and associated with lower disease-free survival.² Co-IP assays indicated that KIF15 presence corresponds with USP14 enzyme presence, leading to increased USP14-AR/AR-V7 complex stabilization and AR deubiquitination.² Western blot showed that KIF15 upregulation is related to AR/AR-V7 upregulation.² KIF15 knockdown in CRPC cells led to smaller tumor volume and weight, improved Enzalutamide effectiveness, and restored sensitivity to Enzalutamide.⁴ KDM4A-AS1 knockdown restores sensitivity to Enzalutamide and decreases CRPC viability.⁴ KDM4A depletion corresponds with increased MDM2, which degrades AR/AR-V7.⁴ Nobiletin addition is beneficial.³ Mice treated with Enzalutamide and Nobiletin, rather than Enzalutamide alone, led to less colony formation by enhancing CRPC sensitivity to Enzalutamide.³ This allows Enzalutamide to exert its inhibitory effects.³ Western blot demonstrated that increasing Nobiletin concentration degrades AR-V7, preventing USP-AR/AR-V7 complex formation.³ Another beneficial addition is Huaier extract.⁵ CCK8 assay showed Enzalutamide cannot decrease CRPC viability.⁵ However, Enzalutamide with Huaier extract decreased cell viability by restoring cell sensitivity to Enzalutamide.⁵ Huaier extract demonstrated antitumor effects, decreased colony numbers, and clones in clonogenic assays.⁵ Huiaer extract demonstrated less CRPC migration and invasion in transwell assays.⁵ An RT-qPCR demonstrated Huiaer extract inhibits USP14, leading to less USP-AR/AR-V7 complex formation or AR/AR-V7 deubiquitination.⁵

Conclusions: Although Lnc-PCBP1-AS1 research is new, solid USP-AR/AR-V7 research regarding CRPC and Enzalutamide resistance exists. Common themes include targeting pathways involved with USP-AR/AR-V7 complex formation. This allows less AR/AR-V7 deubiquitination and instead, ubiquitination and degradation. Clinically, this leads to less CRPC growth, cell viability or proliferation, and restored sensitivity to Enzalutamide, allowing better long-term outcomes for CRPC patients.

Works Cited:

1. Zhang B, Zhang M, Shen C, et al. LncRNA PCBP1-AS1-mediated AR/AR-V7 deubiquitination enhances prostate cancer enzalutamide resistance. Cell Death Dis. 2021;12(10):856. Published 2021 Sep 20. doi:10.1038/s41419-021-04144-2
2. Gao L, Zhang W, Zhang J, et al. KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer. Cancer Res. 2021;81(4):1026-1039. doi:10.1158/0008-5472.CAN-20-1965
3. Liu Y, Yu C, Shao Z, et al. Selective degradation of AR-V7 to overcome castration resistance of prostate cancer. Cell Death Dis. 2021;12(10):857. Published 2021 Sep 21. doi:10.1038/s41419-021-04162-0
4. Zhang B, Zhang M, Yang Y, et al. Targeting KDM4A-AS1 represses AR/AR-Vs deubiquitination and enhances enzalutamide response in CRPC. Oncogene. 2022;41(3):387-399. doi:10.1038/s41388-021-02103-x
5. Liu Z, Liu C, Yan K, Liu J, Fang Z, Fan Y. Huaier Extract Inhibits Prostate Cancer Growth via Targeting AR/AR-V7 Pathway. Front Oncol. 2021;11:615568. Published 2021 Feb 23. doi:10.3389/fonc.2021.615568
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13. Sciarra A, Gentilucci A, Silvestri I, et al. Androgen receptor variant 7 (AR-V7) in sequencing therapeutic agents for castratrion resistant prostate cancer: A critical review. Medicine (Baltimore). 2019;98(19):e15608. doi:10.1097/MD.0000000000015608
14. Wang F, Ning S, Yu B, Wang Y. USP14: Structure, Function, and Target Inhibition. Front Pharmacol. 2022;12:801328. Published 2022 Jan 5. doi:10.3389/fphar.2021.801328