Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Aging-associated ZNF573 methylation regulates RNF19B-PIK3CA ubiquitination to promote prostate cancer

Oncogene (2025)Cite this article

Subjects

Abstract

Aging significantly influences the pathogenesis of prostate cancer (PCa). Emerging evidence suggests that aging-related methylation changes play a critical role in PCa. However, the impact of aging-related DNA methylation in PCa remains largely unexplored. To identify hypermethylated sites associated with aging in PCa, we performed an epigenome-wide analysis using Illumina Human Methylation BeadChip arrays. The candidate methylation markers were further refined through least absolute shrinkage and selection operator (LASSO) regression and Random Forest model. Besides, we investigate the functional role of ZNF573 in PCa. Our analysis identified four aging-related CpG sites in the promoter region of ZNF573 that exhibited significant hypermethylation in PCa. These four DNA methylation markers effectively distinguished PCa from benign prostatic hyperplasia (BPH) with high AUC (0.847), which was superior to PSA. Furthermore, the expression of ZNF573 was notably down-regulated in PCa, and its overexpression significantly inhibited PCa cells proliferation and invasion both in vivo and in vitro. ZNF573 acting as a transcription factor promoted the expression of the E3 ubiquitin ligase RNF19B, which regulated the ubiquitination of PIK3CA. These findings suggest that aging-related ZNF573 methylation could serve as a potential diagnostic biomarker for PCa, influencing the development and progression of PCa through the regulation of PIK3CA ubiquitination via RNF19B.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Epigenome-wide screening of aging-related and differentially expressed DNA methylation sites for PCa.
Fig. 2: Characterization and diagnostic utility of four CpG sites (cg08679971, cg14218481, cg25793785, and cg02349373) in PCa.
Fig. 3: Effects of ZNF573 overexpression on cell proliferation, migration, and invasion.
Fig. 4: Impact of ZNF573 overexpression on tumor growth and metastasis in vivo.
Fig. 5: ZNF573 interacts with and regulates the E3 ubiquitin ligase RNF19B.
Fig. 6: ZNF573 inhibits PIK3CA via enhancing its ubiquitination by RNF19B.

Similar content being viewed by others

Data availability

The data used and/or analyzed in this study are available on request from the corresponding author.

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 Cancer J Clin. 2024;74:229–63.

    PubMed  Google Scholar 

  2. Bergengren O, Pekala KR, Matsoukas K, Fainberg J, Mungovan SF, Bratt O, et al. Update on prostate cancer epidemiology and risk factors—a systematic review. Eur Urol. 2023;84:191–206. 2022.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Behr LC, Simm A, Kluttig A, Grosskopf A. Grosskopf, 60 years of healthy aging: on definitions, biomarkers, scores and challenges. Ageing Res Rev. 2023;88:101934.

    Article  PubMed  Google Scholar 

  4. Liu X, Yu C, Bi Y, Zhang ZJ. Trends and age-period-cohort effect on incidence and mortality of prostate cancer from 1990 to 2017 in China. Public Health. 2019;172:70–80.

    Article  CAS  PubMed  Google Scholar 

  5. Welch HG, Albertsen PC. Reconsidering prostate cancer mortality - the future of PSA screening. N Engl J Med. 2020;382:1557–63.

    Article  PubMed  Google Scholar 

  6. Loeb S, van den Heuvel S, Zhu X, Bangma CH, Schroder FH, Roobol MJ. Infectious complications and hospital admissions after prostate biopsy in a European randomized trial. Eur Urol. 2012;61:1110–4.

    Article  PubMed  Google Scholar 

  7. Lopez-Otin C, Pietrocola F, Roiz-Valle D, Galluzzi L, Kroemer G. Meta-hallmarks of aging and cancer. Cell Metab. 2023;35:12–35.

    Article  CAS  PubMed  Google Scholar 

  8. Mc Auley MT. DNA methylation in genes associated with the evolution of ageing and disease: a critical review. Ageing Res Rev. 2021;72:101488.

    Article  Google Scholar 

  9. Field AE, Robertson NA, Wang T, Havas A, Ideker T, Adams PD. DNA methylation clocks in aging: categories, causes, and consequences. Mol Cell. 2018;71:882–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Li J, Zhu X, Yu K, Jiang H, Zhang Y, Wang B, et al. Exposure to polycyclic aromatic hydrocarbons and accelerated DNA methylation aging. Environ Health Perspect. 2018;126:067005.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Teschendorff AE, Menon U, Gentry-Maharaj A, Ramus SJ, Weisenberger DJ, Shen H, et al. Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. 2010;20:440–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yang PL, Lai TS, Chou YH, Lai LC, Lin SL, Chen YM. DNA methylation in peripheral blood is associated with renal aging and renal function decline: a national community study. Clin Epigenet. 2024;16:80.

    Article  CAS  Google Scholar 

  13. Allen PC, Roberts K, Rubio JE, Tiwari HK, Absher DM, Cooper SJ, et al. Genome-wide DNA methylation analysis implicates enrichment of interferon pathway in African American patients with Systemic Lupus Erythematosus and European Americans with lupus nephritis. J Autoimmun. 2023;139:103089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ma G, Liu H, Hua Q, Wang M, Du M, Lin Y, et al. KCNMA1 cooperating with PTK2 is a novel tumor suppressor in gastric cancer and is associated with disease outcome. Mol Cancer. 2017;16:46.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Che L, Huang J, Lin JX, Xu CY, Wu XM, Du ZB, et al. Aflatoxin B1 exposure triggers hepatic lipotoxicity via p53 and perilipin 2 interaction-mediated mitochondria-lipid droplet contacts: an in vitro and in vivo assessment. J Hazard Mater. 2023;445:130584.

    Article  CAS  PubMed  Google Scholar 

  16. Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013;49:359–67.

    Article  CAS  PubMed  Google Scholar 

  17. Aref-Eshghi E, Schenkel LC, Ainsworth P, Lin H, Rodenhiser DI, Cutz JC, et al. Genomic DNA methylation-derived algorithm enables accurate detection of malignant prostate tissues. Front Oncol. 2018;8:100.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Kirby MK, Ramaker RC, Roberts BS, Lasseigne BN, Gunther DS, Burwell TC, et al. Genome-wide DNA methylation measurements in prostate tissues uncovers novel prostate cancer diagnostic biomarkers and transcription factor binding patterns. BMC Cancer. 2017;17:273.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Li LC, Dahiya R. MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002;18:1427–31.

    Article  CAS  PubMed  Google Scholar 

  20. Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47:W556–W560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Oughtred R, Rust J, Chang C, Breitkreutz BJ, Stark C, Willems A, et al. The BioGRID database: a comprehensive biomedical resource of curated protein, genetic, and chemical interactions. Protein Sci. 2021;30:187–200.

    Article  CAS  PubMed  Google Scholar 

  22. Ying Y, Wang M, Chen Y, Li M, Ma C, Zhang J, et al. Zinc finger protein 280C contributes to colorectal tumorigenesis by maintaining epigenetic repression at H3K27me3-marked loci. Proc Natl Acad Sci USA. 2022;119:e2120633119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Martins F, Rosspopoff O, Carlevaro-Fita J, Forey R, Offner S, Planet E, et al. A cluster of evolutionarily recent krab zinc finger proteins protects cancer cells from replicative stress-induced inflammation. Cancer Res. 2024;84:808–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Arafeh R, Samuels Y. PIK3CA in cancer: the past 30 years. Semin Cancer Biol. 2019;59:36–49.

    Article  CAS  PubMed  Google Scholar 

  25. de Magalhaes JP. How ageing processes influence cancer. Nat Rev Cancer. 2013;13:357–65.

    Article  PubMed  Google Scholar 

  26. Perez RF, Tejedor JR, Fernandez AF, Fraga MF. Aging and cancer epigenetics: where do the paths fork? Aging Cell. 2022;21:e13709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chatsirisupachai K, Palmer D, Ferreira S, de Magalhaes JP. A human tissue-specific transcriptomic analysis reveals a complex relationship between aging, cancer, and cellular senescence. Aging Cell. 2019;18:e13041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chatsirisupachai K, Lesluyes T, Paraoan L, Van Loo P, de Magalhaes JP. An integrative analysis of the age-associated multi-omic landscape across cancers. Nat Commun. 2021;12:2345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bell JT, Tsai PC, Yang TP, Pidsley R, Nisbet J, Glass D, et al. Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLoS Genet. 2012;8:e1002629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yousefi PD, Suderman M, Langdon R, Whitehurst O, Smith GDavey, Relton CL. DNA methylation-based predictors of health: applications and statistical considerations. Nat Rev Genet. 2022;23:369–83.

    Article  CAS  PubMed  Google Scholar 

  31. Wang K, Liu H, Hu Q, Wang L, Liu J, Zheng Z, et al. Epigenetic regulation of aging: implications for interventions of aging and diseases. Signal Transduct Target Ther. 2022;7:374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bell CG, Lowe R, Adams PD, Baccarelli AA, Beck S, Bell JT, et al. DNA methylation aging clocks: challenges and recommendations. Genome Biol. 2019;20:249.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Izadi M, Sadri N, Abdi A, Serajian S, Jalalei D, Tahmasebi S. Epigenetic biomarkers in aging and longevity: current and future application. Life Sci. 2024;351:122842.

    Article  CAS  PubMed  Google Scholar 

  34. Zabransky DJ, Jaffee EM, Weeraratna AT. Shared genetic and epigenetic changes link aging and cancer. Trends Cell Biol. 2022;32:338–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xie W, Kagiampakis I, Pan L, Zhang YW, Murphy L, Tao Y, et al. DNA methylation patterns separate senescence from transformation potential and indicate cancer risk. Cancer Cell. 2018;33:309–21.e305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kwabi-Addo B, Chung W, Shen L, Ittmann M, Wheeler T, Jelinek J, et al. Age-related DNA methylation changes in normal human prostate tissues. Clin Cancer Res. 2007;13:3796–802.

    Article  CAS  PubMed  Google Scholar 

  37. Kumaraswamy A, Welker Leng KR, Westbrook TC, Yates JA, Zhao SG, Evans CP, et al. Recent advances in epigenetic biomarkers and epigenetic targeting in prostate cancer. Eur Urol. 2021;80:71–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Liu MC, Oxnard GR, Klein EA, Swanton C, Seiden MV, Consortium C. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. 2020;31:745–59.

    Article  CAS  PubMed  Google Scholar 

  39. Constancio V, Nunes SP, Moreira-Barbosa C, Freitas R, Oliveira J, Pousa I, et al. Early detection of the major male cancer types in blood-based liquid biopsies using a DNA methylation panel. Clin Epigenetics. 2019;11:175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lomniczi A, Wright H, Castellano JM, Matagne V, Toro CA, Ramaswamy S, et al. Epigenetic regulation of puberty via Zinc finger protein-mediated transcriptional repression. Nat Commun. 2015;6:10195.

    Article  CAS  PubMed  Google Scholar 

  41. Jen J, Wang YC. Zinc finger proteins in cancer progression. J Biomed Sci. 2016;23:53.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Li X, Han M, Zhang H, Liu F, Pan Y, Zhu J, et al. Structures and biological functions of zinc finger proteins and their roles in hepatocellular carcinoma. Biomark Res. 2022;10:2.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Hoover RG, Gullickson G, Kornbluth J. Natural killer lytic-associated molecule plays a role in controlling tumor dissemination and metastasis. Front Immunol. 2012;3:393.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Hoover RG, Gullickson G, Kornbluth J. Impaired NK cytolytic activity and enhanced tumor growth in NK lytic-associated molecule-deficient mice. J Immunol. 2009;183:6913–21.

    Article  CAS  PubMed  Google Scholar 

  45. Li J, Wang H, Lu Q, Han J, Xu H, Sun P. Lysosome-related genes and RNF19 b as prognostic markers for survival and immunotherapy efficacy in hepatocellular carcinoma. Clin Transl Gastroenterol. 2024;15:e1.

    PubMed  PubMed Central  Google Scholar 

  46. Wang Y, Wei M, Su M, Du Z, Dong J, Zhang Y, et al. DIRAS3 enhances RNF19B-mediated RAC1 ubiquitination and degradation in non-small-cell lung cancer cells. iScience. 2023;26:107157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tortorella E, Giantulli S, Sciarra A, Silvestri I. In prostate cancer: a tale of two interconnected pathways. Int J Mol Sci. 2023;24:2046.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Zhou Y, Xu J, Luo H, Meng X, Chen M, Zhu D. Wnt signaling pathway in cancer immunotherapy. Cancer Lett. 2022;525:84–96.

    Article  CAS  PubMed  Google Scholar 

  49. Xue C, Chu Q, Shi Q, Zeng Y, Lu J, Li L. Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances. Signal Transduct Target Ther. 2025;10:106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002;108:837–47.

    Article  CAS  PubMed  Google Scholar 

  51. Soutto M, Peng D, Katsha A, Chen Z, Piazuelo MB, Washington MK, et al. Activation of beta-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis. Gut. 2015;64:1028–39.

    Article  CAS  PubMed  Google Scholar 

  52. Li H, Liu S, Jin R, Xu H, Li Y, Chen Y, et al. Pyrvinium pamoate regulates MGMT expression through suppressing the Wnt/beta-catenin signaling pathway to enhance the glioblastoma sensitivity to temozolomide. Cell Death Discov. 2021;7:288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the Fundamental Research Funds for the Central Universities (JUSRP11951).

Author information

Author notes

  1. These authors contributed equally: Yuqiu Ge, Peiyu Han, Yangyang Sun.

Authors and Affiliations

  1. Department of Urology, Pukou Hospital of Chinese Medicine Affiliated to China Pharmaceutical University, Nanjing, China

    Yuqiu Ge, Yangyang Sun, Qinbo Yuan & Gaoxiang Ma

  2. Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China

    Yuqiu Ge, Peiyu Han & Yuyu Chen

  3. Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, China

    Yangyang Sun

  4. Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China

    Qianqian Shi & Li Cui

  5. Department of Urology, Wuxi Fifth People’s Hospital, Wuxi, China

    Qinbo Yuan

  6. State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China

    Gaoxiang Ma

Authors
  1. Yuqiu Ge
    View author publications

    Search author on:PubMed Google Scholar

  2. Peiyu Han
    View author publications

    Search author on:PubMed Google Scholar

  3. Yangyang Sun
    View author publications

    Search author on:PubMed Google Scholar

  4. Yuyu Chen
    View author publications

    Search author on:PubMed Google Scholar

  5. Qianqian Shi
    View author publications

    Search author on:PubMed Google Scholar

  6. Li Cui
    View author publications

    Search author on:PubMed Google Scholar

  7. Qinbo Yuan
    View author publications

    Search author on:PubMed Google Scholar

  8. Gaoxiang Ma
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Study conception and design: GM, YG. Acquisition and analysis of data: YG, PH, YS. Drafting and revision of the manuscript: YG, GM, LC, QY. Administrative, technical or material support: YC, QS, LC, QY. Study supervision: GM. Final approval of the manuscript: all authors.

Corresponding authors

Correspondence to Li Cui, Qinbo Yuan or Gaoxiang Ma.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All subjects provided written informed consent prior to enrollment. The study protocol was approved by the Institutional Review Board of the Third Affiliated Hospital of Soochow University (CL022H71-01). All animal experiments were performed in accordance with protocols approved by the Animal Care Committee of Jiangnan University and in compliance with the guidelines set by the Institutional Animal Care and Use Committee (JN. No20230215b0320915[025]).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ge, Y., Han, P., Sun, Y. et al. Aging-associated ZNF573 methylation regulates RNF19B-PIK3CA ubiquitination to promote prostate cancer. Oncogene (2025). https://doi.org/10.1038/s41388-025-03579-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41388-025-03579-7

Search

Advanced search

Quick links