Background: Prostate cancer (PCa) is a leading malignancy in men, with a poor prognosis in the advanced stage. Aly/REF export factor (ALYREF), a 5-methylcytosine (m5C)-binding protein regulating RNA export, has been implicated in several cancers. This study aimed to clarify the role of ALYREF in PCa progression and prognosis. Methods: We integrated multi-omics datasets from The Cancer Genome Atlas (TCGA), Stand Up To Cancer (SU2C), Genotype-Tissue Expression (GTEx), and Cancer Dependency Map (DepMap) with immunohistochemistry and in vitro assays. Survival outcomes were analyzed using Kaplan-Meier and Cox regression. Functional enrichment assessed ALYREF-associated pathways, while ALYREF knockdown in LNCaP and enzalutamide-resistant cells evaluated its oncogenic role. Results: ALYREF was significantly upregulated in multiple cancer types and correlated with poor prognosis in PCa. High ALYREF expression predicted biochemical recurrence in localized PCa and shorter progression-free and overall survival in advanced PCa. Multi-omics profiling revealed enrichment in MYC targets, oxidative phosphorylation, E2F signaling, and mTORC1 pathways. DepMap data showed that ALYREF is essential for tumor cell proliferation, with high dependency in PCa lines. Consistently, ALYREF knockdown suppressed cell viability and clonogenic growth in both hormone-sensitive and resistant models. Conclusions: This study identifies ALYREF as an oncogenic driver and unfavorable prognostic biomarker in PCa. Integrating multi-omics evidence with functional validation, ALYREF emerges as a promising therapeutic target, particularly in advanced and therapy-resistant PCa.
Cai et al. (Wed,) studied this question.