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Original Research

Open Access Special Issue

ALYREF correlates with tumor progression and therapy resistance in localized and advanced prostate cancer

  • Zhouda Cai1,†
  • Yu Liu2,†
  • Shengda Song3
  • Chuanfan Zhong1
  • Jiahong Chen4
  • Le Zhang5
  • Chao Cai2
  • Jianming Lu1
  • Yanru Zeng1,6,*,
  • Weide Zhong1,2,*,

1Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, Guangzhou Medical University, 510180 Guangzhou, Guangdong, China

2Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou Institute of Urology, 510230 Guangzhou, Guangdong, China

3Department of Urology, Meizhou People’s Hospital (Huangtang Hospital), 514000 Meizhou, Guangdong, China

4Department of Urology, Huizhou Central People’s Hospital, 516000 Huizhou, Guangdong, China

5Institute for Integrative Genome Biology, University of California, Riverside, CA 92507, USA

6Institute of Gerontology, Guangzhou Geriatric Hospital, Guangzhou Medical University, 510550 Guangzhou, Guangdong, China

DOI: 10.22514/jomh.2026.033 Vol.22,Issue 4,April 2026 pp.42-52

Submitted: 10 October 2025 Accepted: 16 December 2025

Published: 30 April 2026

*Corresponding Author(s): Yanru Zeng E-mail: Jolene@gzhmu.edu.cn
*Corresponding Author(s): Weide Zhong E-mail: eyweidezhong@scut.edu.cn

† These authors contributed equally.

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Abstract

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.


Keywords

ALYREF; Prostate cancer; Biomarkers; Multi-omics analysis


Cite and Share

Zhouda Cai,Yu Liu,Shengda Song,Chuanfan Zhong,Jiahong Chen,Le Zhang,Chao Cai,Jianming Lu,Yanru Zeng,Weide Zhong. ALYREF correlates with tumor progression and therapy resistance in localized and advanced prostate cancer. Journal of Men's Health. 2026. 22(4);42-52.

URL:

https://www.jomh.org/articles/10.22514/jomh.2026.033

References

[1] Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2024; 74: 229–263.

[2] Cornford P, van den Bergh RCN, Briers E, Van den Broeck T, Brunckhorst O, Darraugh J, et al. EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on prostate cancer—2024 update. Part I: screening, diagnosis, and local treatment with curative intent. European Urology. 2024; 86: 148–163.

[3] Yin W, Chen G, Li Y, Li R, Jia Z, Zhong C, et al. Identification of a 9-gene signature to enhance biochemical recurrence prediction in primary prostate cancer: a benchmarking study using ten machine learning methods and twelve patient cohorts. Cancer Letters. 2024; 588: 216739.

[4] Liu D, Wang L, Guo Y. Advances in and prospects of immunotherapy for prostate cancer. Cancer Letters. 2024; 601: 217155.

[5] Chen Y, Long T, Wang M, Liu S, Lv Z, Jiang Y, et al. Prospective cohort study integrating plasma proteomics and machine learning for early risk prediction of prostate cancer. International Journal of Surgery. 2025; 111: 6123–6134.

[6] Li C, Wu L, Zhong B, Gan Y, Zhou L, Tan S, et al. Integrated multi-omics profiling of immune microenvironment and drug resistance signatures for precision prognosis in prostate cancer. Cancer Drug Resistance. 2025; 8: 31.

[7] Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discovery. 2022; 12: 31–46.

[8] Liu WW, Zheng SQ, Li T, Fei YF, Wang C, Zhang S, et al. RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy. Signal Transduction and Targeted Therapy. 2024; 9: 70.

[9] Tan X, Cai Z, Chen G, Cai C, Chen J, Liang Y, et al. Identification and verification of an ALYREF-involved 5-methylcytosine based signature for stratification of prostate cancer patients and prediction of clinical outcome and response to therapies. Discover Oncology. 2023; 14: 62.

[10] Cai Z, Jiang Z, Li S, Mo S, Wang S, Liang M, et al. RNA modification Regulators’ Co-Expression Score (RMRCoeS) predicts biochemical recurrence and therapy response in prostate cancer: a multi-omics and experimental validation study. International Immunopharmacology. 2024; 139: 112723.

[11] Wang W, Ding Y, Zhao H, Wang S, Huang J, Sun L. NSUN2-tRNAVal-CAC-axis-regulated codon-biased translation drives triple-negative breast cancer glycolysis and progression. Cellular & Molecular Biology Letters. 2025; 30: 100.

[12] Gao X, Shen Y, Xiao Z, Han Z, Liu X, Cai A, et al. Preservation of ALYREF phase separation mitigates doxorubicin-induced cardiomyocyte DNA damage and cardiotoxicity. Advanced Science. 2025; 12: e05270.

[13] Li R, Zhu J, Zhong WD, Jia Z. Comprehensive evaluation of machine learning models and gene expression signatures for prostate cancer prognosis using large population cohorts. Cancer Research. 2022; 82: 1832–1843.

[14] Mayakonda A, Lin DC, Assenov Y, Plass C, Koeffler HP. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Research. 2018; 28: 1747–1756.

[15] Gu Z. Complex heatmap visualization. Imeta. 2022; 1: e43.

[16] Xu S, Hu E, Cai Y, Xie Z, Luo X, Zhan L, et al. Using clusterProfiler to characterize multiomics data. Nature Protocols. 2024; 19: 3292–3320.

[17] Zhang J, Li H, Tao W, Zhou J. GseaVis: an R package for enhanced visualization of gene set enrichment analysis in biomedicine. Med Research. 2025; 1: 131–135.

[18] Zhong C, Wang J, Peng H, Lu J, Long Z, Lin Z, et al. GG-NER’s role in androgen receptor signaling inhibitor response for advanced prostate cancer. Cell Communication and Signaling. 2024; 22: 600.

[19] Zhong C, Long Z, Yang T, Wang S, Zhong W, Hu F, et al. M6A-modified circRBM33 promotes prostate cancer progression via PDHA1-mediated mitochondrial respiration regulation and presents a potential target for ARSI therapy. International Journal of Biological Sciences. 2023; 19: 1543–1563.

[20] Sartor O. Localized prostate cancer—then and now. The New England Journal of Medicine. 2023; 388: 1617–1618.

[21] Cai M, Song XL, Li XA, Chen M, Guo J, Yang DH, et al. Current therapy and drug resistance in metastatic castration-resistant prostate cancer. Drug Resistance Updates. 2023; 68: 100962.

[22] Khorasanchi A, Hong F, Yang Y, Singer EA, Wang P, Li M, et al. Overcoming drug resistance in castrate-resistant prostate cancer: current mechanisms and emerging therapeutic approaches. Cancer Drug Resistance. 2025; 8: 9.

[23] Shagera QA, Karfis I, Kristanto P, Spyridon S, Diamand R, Santapau A, et al. PSMA PET/CT for response assessment and overall survival prediction in patients with metastatic castration-resistant prostate cancer treated with androgen receptor pathway inhibitors. Journal of Nuclear Medicine. 2023; 64: 1869–1875.

[24] Shi M, Zhang H, Wu X, He Z, Wang L, Yin S, et al. ALYREF mainly binds to the 5′ and the 3′ regions of the mRNA in vivo. Nucleic Acids Research. 2017; 45: 9640–9653.

[25] Pacheco-Fiallos B, Vorländer MK, Riabov-Bassat D, Fin L, O’Reilly FJ, Ayala FI, et al. mRNA recognition and packaging by the human transcription-export complex. Nature. 2023; 616: 828–835.

[26] Fan J, Wang K, Du X, Wang J, Chen S, Wang Y, et al. ALYREF links 3′-end processing to nuclear export of non-polyadenylated mRNAs. The EMBO Journal. 2019; 38: e99910.

[27] Cai D, Chen X, Xu H, Zhao Q, Zhou X, Wu J, et al. m5C-modified circRREB1 promotes lung cancer progression by inducing mitophagy. Journal of Experimental & Clinical Cancer Research. 2025; 44: 203.

[28] Xu D, Fu Y, Sun H, Lu Y, Shen B, Hao X. ALYREF stabilizes CREPT mRNA to accelerate the development of nasopharyngeal carcinoma through dependence on m5C modification. Experimental Cell Research. 2025; 452: 114747.

[29] Shi CJ, Pang FX, Lei YH, Deng LQ, Pan FZ, Liang ZQ, et al. 5-methylcytosine methylation of MALAT1 promotes resistance to sorafenib in hepatocellular carcinoma through ELAVL1/SLC7A11-mediated ferroptosis. Drug Resistance Updates. 2025; 78: 101181.

[30] Cheng J, He Z, Jing J, Liu Y, Zhang H. Integrating machine learning and multi-omics to identify key SUMOylation molecular signature in sarcoma. Life Conflux. 2024; 1: e88.

[31] Huang C, Liu Z, Guo Y, Wang W, Yuan Z, Guan Y, et al. scCancerExplorer: a comprehensive database for interactively exploring single-cell multi-omics data of human pan-cancer. Nucleic Acids Research. 2025; 53: D1526–D1535.

[32] Xie J, Xie Y, Tan W, Ye Y, Ou X, Zou X, et al. Deciphering the role of ELAVL1: insights from pan-cancer multiomics analyses with emphasis on nasopharyngeal carcinoma. Journal of Translational Internal Medicine. 2025; 13: 138–155.

[33] Zhang Y, Chen XN, Zhang H, Wen JK, Gao HT, Shi B, et al. CDK13 promotes lipid deposition and prostate cancer progression by stimulating NSUN5-mediated m5C modification of ACC1 mRNA. Cell Death & Differentiation. 2023; 30: 2462–2476.

[34] Garcia-Martin R, Wang G, Brandão BB, Zanotto TM, Shah S, Kumar Patel S, et al. MicroRNA sequence codes for small extracellular vesicle release and cellular retention. Nature. 2022; 601: 446–451.


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