Related Experiment Video
Updated: Jun 23, 2025
Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
SYT4 binds to SNAP25 to facilitate exosomal secretion and prostate cancer enzalutamide resistance
Budeng Huang1, Xiyue Deng1, Guochao Zhou2
1Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Abstract:
Prostate carcinoma represents a predominant malignancy affecting the male population, with androgen deprivation therapy (ADT) serving as a critical therapeutic modality for advanced disease states, but it often leads to the development of resistance. Enzalutamide (Enz), a second-generation antiandrogen drug, initially offers substantial therapeutic benefit, but its efficacy wanes as drug resistance ensues. In this study, we found that synaptotagmin 4 (SYT4) is an upregulated gene in enzalutamide-resistant (EnzR) cell lines. The downregulation of SYT4, in combination with enzalutamide therapy, substantially enhances the antiproliferative effect on resistant prostate cancer cells beyond the capacity of enzalutamide monotherapy. SYT4 promotes vesicle efflux by binding to the synaptosome-associated protein 25 (SNAP25), thereby contributing to cell resistance against enzalutamide. The elevated expression of SYT4 is mediated by bromodomain-containing protein 4 (BRD4), and BRD4 inhibition effectively suppressed the expression of SYT4. Treatment with a therapeutic dose of enzalutamide combined with ASO-1, an antisense oligonucleotide drug targeting SYT4, shows promising results in reversing the resistance of prostate cancer to enzalutamide.
Insights
Synaptotagmin 4 (SYT4) drives resistance to enzalutamide in prostate cancer. Inhibiting SYT4 with antisense oligonucleotides alongside enzalutamide shows promise in overcoming treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate carcinoma is a leading male cancer, often treated with androgen deprivation therapy (ADT).
- Enzalutamide (Enz), an antiandrogen, is effective but resistance develops in advanced prostate cancer.
- Understanding resistance mechanisms is crucial for improving treatment efficacy.
Purpose of the Study:
- To identify genes involved in enzalutamide resistance in prostate cancer.
- To investigate the role of synaptotagmin 4 (SYT4) in mediating enzalutamide resistance.
- To explore therapeutic strategies targeting SYT4 to overcome enzalutamide resistance.
Main Methods:
- Analysis of gene expression in enzalutamide-resistant (EnzR) prostate cancer cell lines.
- Investigating the interaction between SYT4 and synaptosome-associated protein 25 (SNAP25).
- Evaluating the effect of SYT4 downregulation and bromodomain-containing protein 4 (BRD4) inhibition on cell proliferation.
- Assessing the efficacy of combined enzalutamide and SYT4-targeting antisense oligonucleotide (ASO-1) therapy.
Main Results:
- Synaptotagmin 4 (SYT4) was found to be upregulated in EnzR cell lines.
- SYT4 downregulation, combined with enzalutamide, significantly enhanced antiproliferative effects in resistant cells.
- SYT4 promotes vesicle efflux via SNAP25, contributing to enzalutamide resistance.
- Bromodomain-containing protein 4 (BRD4) mediates elevated SYT4 expression; BRD4 inhibition suppressed SYT4.
- Combined therapy with enzalutamide and ASO-1 showed promise in reversing resistance.
Conclusions:
- SYT4 is a key mediator of enzalutamide resistance in prostate cancer.
- Targeting SYT4, potentially through BRD4 inhibition or antisense oligonucleotides, represents a viable strategy to overcome treatment resistance.
- Combination therapy holds potential for improving outcomes in advanced prostate cancer.
