Elevated VRK1 levels after androgen deprivation therapy promote prostate cancer progression by upregulating YAP1 expression

Purpose: Vaccinia-related kinase 1 (VRK1) is a serine-threonine kinase involved in the proliferation and migration of various Cancer cells. However, its role in prostate Cancer (PCa), particularly in the development of therapeutic resistance, remains unclear.

Methods: We established an androgen-independent PCa cell line derived from LNCaP prostate Cancer cells and conducted transcriptome and proteome Sequencing together with bioinformatic analyses of large clinical sample databases to investigate the potential role of VRK1 in PCa progression. The correlation between VRK1 and Androgen Receptor (AR) signaling was evaluated under simulated clinical treatment conditions. The effects of VRK1 on cell proliferation were assessed in vitro and in vivo using Cell Counting Kit-8 and colony formation assays. Additionally, proteome and transcriptome Sequencing, combined with rescue experiments were performed to explore VRK1-regulated signaling pathways related to cell proliferation and therapeutic resistance.

Results: VRK1 expression was elevated during the progression of androgen-dependent prostate Cancer to castration-resistant prostate Cancer under therapeutic conditions, and high VRK1 expression was associated with a poor prognosis in patients with PCa. VRK1 was regulated by AR signaling, and its silencing suppressed PCa cell proliferation both in vitro and in vivo. VRK1 drove cell proliferation and therapeutic resistance in PCa by modulating yes-associated protein 1 (YAP1).

Conclusions: VRK1 serves as a prognostic marker in PCa, regulated by AR signaling. VRK1 depletion inhibited cell proliferation both in vitro and in vivo, while elevated VRK1 upregulated YAP1, promoting cell proliferation and therapeutic resistance.

AR; Castration-resistant; Prostate cancer; VRK1; YAP1.