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Lysine methyltransferase SMYD2 enhances androgen receptor signaling to modulate CRPC cell resistance to enzalutamide

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Abstract

Androgen receptors (ARs) play key roles in prostate cancer (PCa) progression and castration-resistant prostate cancer (CRPC) resistance to drug therapy. SET and MYND domain containing protein 2 (SMYD2), a lysine methyltransferase, has been reported to promote tumors by transcriptionally methylating important oncogenes or tumor repressor genes. However, the role of SMYD2 in CRPC drug resistance remains unclear. In this study, we found that SMYD2 expression was significantly upregulated in PCa tissues and cell lines. High SMYD2 expression indicated poor CRPC-free survival and overall survival in patients. SMYD2 knockdown dramatically inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) potential of 22Rv1 and C4-2 cells. Conversely, ectopic overexpression of SMYD2 promoted these effects in 22Rv1 and C4-2 cells. Mechanistically, SMYD2 methylated and phosphorylated ARs to affect AR ubiquitination and proteasome degradation, which further alters the AR transcriptome in CRPC cells. Importantly, the SMYD2 inhibitor AZ505 had a synergistic therapeutic effect with enzalutamide in CRPC cells and mouse models; however, it could also re-sensitize resistant CRPC cells to enzalutamide. Our findings demonstrated that SMYD2 enhances the methylation and phosphorylation of ARs and affects AR ubiquitination and proteasome degradation to modulate CRPC cell resistance to enzalutamide, indicating that SMYD2 serves as a crucial oncogene in PCa and is an ideal therapeutic target for CRPC.

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Fig. 1: SMYD2 expression is upregulated and associated with poor prognosis in PCa.
Fig. 2: Abnormally overexpressed SMYD2 results in PCa progression.
Fig. 3: SMYD2 physically interacts with AR and regulates the AR methylation.
Fig. 4: SMYD2 regulates AR degradation and signaling.
Fig. 5: SMYD2 knockdown reduces AR binding to DNA and expression of corresponding genes.
Fig. 6: Pharmacological intervention of SMYD2 synergizes enzalutamide in CRPC cells.
Fig. 7: A working model of the SMYD2-AR signaling pathway modulating CRPC cell resistance to enzalutamide.

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Data availability

All data that support the findings of this study are available from the corresponding authors upon reasonable request. The accession numbers of the RNA-seq data and ChIP-seq data is SRA: PRJNA963230.

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Funding

This study was supported by grants from the National Nature Science Foundation of China (82373355, 82172703, and 82303856), the Medical Innovation Research Project of the Science and Technology Commission of Shanghai Municipality (20Y11905000), the Discipline Leader of Shanghai Municipal Health Commission (2022XD013), the China Anti-cancer Association Foundation (YJQN202201), and the Shanghai Sailing Program (20YF1443800).

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  1. These authors contributed equally: Junhong Li, Zhe Hong.

Authors and Affiliations

  1. Department of Urology, Fudan University Shanghai Cancer Center, 200032, Shanghai, China

    Junhong Li, Zhe Hong, Junyu Zhang, Shengfeng Zheng, Fangning Wan, Zheng Liu & Bo Dai

  2. Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China

    Junhong Li, Zhe Hong, Junyu Zhang, Shengfeng Zheng, Fangning Wan, Zheng Liu & Bo Dai

  3. Shanghai Genitourinary Cancer Institute, 200032, Shanghai, China

    Junhong Li, Zhe Hong, Junyu Zhang, Shengfeng Zheng, Fangning Wan, Zheng Liu & Bo Dai

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  1. Junhong Li
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Contributions

BD and ZH contributed to conceptualization, funding acquisition and project administration. JHL, JYZ, and SFZ performed the in vitro experiments and analyzed data. ZL, FNW, and JHL performed the in vivo experiments. ZH and JHL drafted the initial manuscript and BD critically revised it. All authors read and approved the final manuscript.

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Correspondence to Zhe Hong or Bo Dai.

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The authors declare no competing interests.

Ethics approval

This study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (No. 050432-4-1911D), following the Declaration of Helsinki, and written informed consent was obtained from each patient. For the mouse experiments, all animals were housed under a specific pathogen-free environment, and all in vivo experiments were reviewed and approved by the Institutional Animal Care and Use Committee of the Fudan University Shanghai Cancer Center (FUSCC-IACUC-2022035).

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Li, J., Hong, Z., Zhang, J. et al. Lysine methyltransferase SMYD2 enhances androgen receptor signaling to modulate CRPC cell resistance to enzalutamide. Oncogene 43, 744–757 (2024). https://doi.org/10.1038/s41388-024-02945-1

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