Skip to main content

Thank you for visiting 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.

DNMT1-mediated epigenetic silencing of TRAF6 promotes prostate cancer tumorigenesis and metastasis by enhancing EZH2 stability


A plethora of studies have shown that both DNMT1 and EZH2 have great effects on the progression of a variety of cancers. However, it remains unclear whether the expression profiles of these two epigenetic enzymes are molecularly intertwined in prostate cancer (PC), especially in castration-resistant prostate cancer (CRPC). Here, we found that DNMT1 is highly expressed and facilitates PC cell proliferation and migration. Importantly, we demonstrate that the abrogation of DNMT1 expression can induce the decreased expression of EZH2, resulting in the less aggressive capacity of PC cells. Mechanistically, we discovered that DNMT1 promotes PC tumorigenesis and metastasis by inhibiting TRAF6 transcriptional expression and subsequent TRAF6-mediated EZH2 ubiquitination. Finally, we confirmed that there is a negative correlation between DNMT1 and TRAF6 expression and a positive correlation between DNMT1 and EZH2 expression in PC patients. In this study, we first disclose that there is a direct crosstalk between DNA methyltransferase DNMT1 expression and histone methyltransferase EZH2 expression in tumorigenesis and cancer metastasis in vitro and in vivo. Our results also show that targeting DNMT1 with its inhibitor decitabine (an FDA-approved drug) is an appealing treatment strategy for CRPC patients through epigenetic suppression of both DNMT1-mediated DNA methylation and EZH2-modulated histone methylation.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: DNMT1 promotes prostate cancer cell proliferation in vitro.
Fig. 2: DNMT1 promotes prostate cancer cell invasion and migration in vitro.
Fig. 3: DNMT1 strengthens EZH2 protein stability by inhibiting its ubiquitination degradation.
Fig. 4: DNMT1 suppresses TRAF6 transcription expression, which leads to attenuating TRAF6-mediated EZH2 ubiquitination degradation.
Fig. 5: EZH2 is required for DNMT1-promoting prostate cancer cell proliferation and motility in vitro.
Fig. 6: DNMT1 promotes prostate cancer tumorigenesis and metastasis by enhancing EZH2 stability.
Fig. 7: DNMT1-TRAF6-EZH2 axis correlated with prostate cancer patient clinicopathological characteristics.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.


  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71:7–33.

    Article  Google Scholar 

  2. Attard G, Parker C, Eeles RA, Schroder F, Tomlins SA, Tannock I, et al. Prostate cancer. Lancet. 2016;387:70–82.

    Article  Google Scholar 

  3. Teo MY, Rathkopf DE, Kantoff P. Treatment of advanced prostate cancer. Annu Rev Med. 2019;70:479–99.

    Article  CAS  Google Scholar 

  4. Tzelepi V, Logotheti S, Efstathiou E, Troncoso P, Aparicio A, Sakellakis M, et al. Epigenetics and prostate cancer: defining the timing of DNA methyltransferase deregulation during prostate cancer progression. Pathology. 2020;52:218–27.

    Article  CAS  Google Scholar 

  5. Agarwal S, Amin KS, Jagadeesh S, Baishay G, Rao PG, Barua NC, et al. Mahanine restores RASSF1A expression by down-regulating DNMT1 and DNMT3B in prostate cancer cells. Mol Cancer. 2013;12:99.

    Article  Google Scholar 

  6. Lyko F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet. 2018;19:81–92.

    Article  CAS  Google Scholar 

  7. Wong KK. DNMT1: a key drug target in triple-negative breast cancer. Semin Cancer Biol. 2021;72:198–213.

    Article  CAS  Google Scholar 

  8. Zhu A, Hopkins KM, Friedman RA, Bernstock JD, Broustas CG, Lieberman HB. DNMT1 and DNMT3B regulate tumorigenicity of human prostate cancer cells by controlling RAD9 expression through targeted methylation. Carcinogenesis. 2021;42:220–31.

    Article  CAS  Google Scholar 

  9. Liu H, Song Y, Qiu H, Liu Y, Luo K, Yi Y, et al. Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis. Cell Death Differ. 2020;27:966–83.

    Article  CAS  Google Scholar 

  10. Dhillon S. Decitabine/cedazuridine: first approval. Drugs. 2020;80:1373–8.

    Article  CAS  Google Scholar 

  11. DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133:7–17.

    Article  CAS  Google Scholar 

  12. Garcia-Manero G, Griffiths EA, Steensma DP, Roboz GJ, Wells R, McCloskey J, et al. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood. 2020;136:674–83.

    Article  CAS  Google Scholar 

  13. Montesinos P, Roboz GJ, Bulabois CE, Subklewe M, Platzbecker U, Ofran Y, et al. Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study. Leukemia. 2021;35:62–74.

    Article  CAS  Google Scholar 

  14. Yu J, Qin B, Moyer AM, Nowsheen S, Liu T, Qin S, et al. DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine. J Clin Invest. 2018;128:2376–88.

    Article  Google Scholar 

  15. Li ZW, Li ML, Wang DD, Hou PF, Chen XT, Chu SF, et al. Post-translational modifications of EZH2 in cancer. Cell Biosci. 2020;10:143.

    Article  Google Scholar 

  16. Chang CJ, Hung MC. The role of EZH2 in tumour progression. Br J Cancer. 2012;106:243–7.

    Article  CAS  Google Scholar 

  17. Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med. 2016;22:128–34.

    Article  CAS  Google Scholar 

  18. Li Z, Hou P, Fan D, Dong M, Ma M, Li H, et al. The degradation of EZH2 mediated by lncRNA ANCR attenuated the invasion and metastasis of breast cancer. Cell Death Differ. 2017;24:59–71.

    Article  Google Scholar 

  19. Li Z, Wang D, Lu J, Huang B, Wang Y, Dong M, et al. Methylation of EZH2 by PRMT1 regulates its stability and promotes breast cancer metastasis. Cell Death Differ. 2020;27:3226–42.

    Article  CAS  Google Scholar 

  20. Li ZW, Wang DD, Wang WW, Chen XT, Tang AQ, Hou PF, et al. Macrophages-stimulated PRMT1-mediated EZH2 methylation promotes breast cancer metastasis. Biochem Biophys Res Commun. 2020;533:679–84.

    Article  CAS  Google Scholar 

  21. Li ZW, Wang DD, Chen XT, Wang WW, Wang PF, Hou PF, et al. PRMT1-mediated EZH2 methylation promotes breast cancer cell proliferation and tumorigenesis. Cell Death Dis. 2021;12:1080.

    Article  Google Scholar 

  22. Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419:620–4.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Klutstein M, Nejman D, Greenfield R, Cedar H. DNA methylation in cancer and aging. Cancer Res. 2016;76:3446–50.

    Article  CAS  Google Scholar 

  25. Mao L, Yu H, Ma S, Xu Z, Wei F, Yang C, et al. Combination of oncolytic adenovirus targeting SATB1 and docetaxel for the treatment of castration-resistant prostate cancer. J Cancer. 2021;12:1846–52.

    Article  CAS  Google Scholar 

  26. Chen X, Li Z, Yong H, Wang W, Wang D, Chu S, et al. Trim21-mediated HIF-1alpha degradation attenuates aerobic glycolysis to inhibit renal cancer tumorigenesis and metastasis. Cancer Lett. 2021;508:115–26.

    Article  CAS  Google Scholar 

  27. Li Z, Dong M, Fan D, Hou P, Li H, Liu L, et al. LncRNA ANCR down-regulation promotes TGF-beta-induced EMT and metastasis in breast cancer. Oncotarget. 2017;8:67329–43.

    Article  Google Scholar 

  28. Bai J, Wu K, Cao MH, Yang YY, Pan Y, Liu H, et al. SCFFBXO22 targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis. Proc Natl Acad Sci USA. 2019;116:11754–63.

    Article  CAS  Google Scholar 

Download references


We thank Professor Zhenbang Chen (Meharry Medical College) for providing the TRAF6 plasmid. We sincerely appreciate the researchers who worked on this experiment.


This work was supported by grants from the National Natural Science Foundation of China (82173060 and 82072649), the Outstanding Youth Foundation of Jiangsu Province (BK20200046), the National Postdoctoral Research Funds of China (2019M651971 and 2021T140577), the Postgraduate Research & Practice Innovation Program of Jiangsu (KYCX21_2689), the Jiangsu Provincial Key Medical Discipline, the Project of Invigorating Health Care through Science, Technology and Education (NO. ZDXKA2016014) and the Qinglan Project of Jiangsu.

Author information

Authors and Affiliations



ZL, JB, JZ and LM provided the study concept and design. ZL, BL and HY collected and analysed the data. ZL, BL and PW interpreted the data. ZL, BL, HY, PW, ML, SC and PH performed the experiments. ZL and BL wrote the manuscript. ZL, JB, JZ and LM revised the manuscript. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Junnian Zheng, Lijun Mao or Jin Bai.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study was conducted in compliance with the Declaration of Helsinki. Informed consent was obtained from all subjects. The ethics approval statements for human subjects were provided by the Ethnic Committee of the Affiliated Hospital of Xuzhou Medical University. The ethics approval statements for animal work were provided by the Institutional Animal Care and Use Committee of Xuzhou Medical University.

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

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, Z., Li, B., Yu, H. et al. DNMT1-mediated epigenetic silencing of TRAF6 promotes prostate cancer tumorigenesis and metastasis by enhancing EZH2 stability. Oncogene 41, 3991–4002 (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links