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

Abstract

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.

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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.

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Acknowledgements

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

Funding

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.

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Contributions

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.

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The authors declare no competing interests.

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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.

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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). https://doi.org/10.1038/s41388-022-02404-9

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