SYT4 binds to SNAP25 to facilitate exosomal secretion and prostate cancer enzalutamide resistance

• Published in: Cancer science Vol. 115; no. 8; pp. 2630 - 2645
• Main Authors: Huang, Budeng, Deng, Xiyue, Zhou, Guochao, Li, Keqiang, Feng, Yuankang, Xie, Guoqing, Liu, Ruoyang, Song, Liang, Huang, Zhenlin, Jia, Zhankui
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.08.2024
• Subjects: Androgens; Animals; Antisense oligonucleotides; Antisense therapy; Benzamides; BRD4; Bromodomain Containing Proteins; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Disease resistance; Drug resistance; Drug Resistance, Neoplasm; enzalutamide resistance; exosome; Exosomes - drug effects; Exosomes - metabolism; Extracellular vesicles; Gene amplification; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Humans; Male; Malignancy; Medical prognosis; Metastasis; Mice; Nitriles; Phenylthiohydantoin - pharmacology; Prostate cancer; Prostate carcinoma; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; SNAP-25 protein; SNAP25; Synaptosomal-Associated Protein 25; Synaptotagmin; Synaptotagmins - genetics; Synaptotagmins - metabolism; SYT4; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor cell lines; SNAP25; SYT4; exosome; enzalutamide resistance; BRD4
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.16239

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. Our research reveals that under the influence of BRD4, the prominently expressed SYT4 protein facilitates the release of exosomes encapsulating enzalutamide by binding to the cell membrane surface protein SNAP25, promoting enzalutamide efflux and inducing resistance in prostate cancer. The research lays the groundwork for the design of corresponding antisense oligonucleotide (ASO) drugs as a potential therapeutic approach for patients with enzalutamide‐resistant prostate cancer.