The ELAVL3/MYCN positive feedback loop provides a therapeutic target for neuroendocrine prostate cancer

Yiyi Ji, Weiwei Zhang, Kai Shen, Ruopeng Su, Xinyu Liu, Zehua Ma, Bo Liu, Cong Hu, Yizheng Xue, Zhixiang Xin, Yi Yang, Ang Li, Zhou Jiang, Na Jing, Helen He Zhu, Liang Dong, Yinjie Zhu, Baijun Dong, Jiahua Pan, Qi Wang () and Wei Xue ()
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Yiyi Ji: Shanghai Jiao Tong University School of Medicine
Weiwei Zhang: Shanghai Jiao Tong University School of Medicine
Kai Shen: Shanghai Jiao Tong University School of Medicine
Ruopeng Su: Shanghai Jiao Tong University School of Medicine
Xinyu Liu: Shanghai Jiao Tong University School of Medicine
Zehua Ma: Shanghai Jiao Tong University School of Medicine
Bo Liu: Shanghai Jiao Tong University School of Medicine
Cong Hu: Shanghai Jiao Tong University School of Medicine
Yizheng Xue: Shanghai Jiao Tong University School of Medicine
Zhixiang Xin: Shanghai Jiao Tong University School of Medicine
Yi Yang: Shanghai Jiao Tong University School of Medicine
Ang Li: Shanghai Jiao Tong University School of Medicine
Zhou Jiang: Shanghai Jiao Tong University School of Medicine
Na Jing: Shanghai Jiao Tong University School of Medicine
Helen He Zhu: Shanghai Jiao Tong University School of Medicine
Liang Dong: Shanghai Jiao Tong University School of Medicine
Yinjie Zhu: Shanghai Jiao Tong University School of Medicine
Baijun Dong: Shanghai Jiao Tong University School of Medicine
Jiahua Pan: Shanghai Jiao Tong University School of Medicine
Qi Wang: Shanghai Jiao Tong University School of Medicine
Wei Xue: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract Neuroendocrine prostate cancer is a rapidly progressive and lethal disease characterized by early visceral metastasis, poor prognosis, and limited treatment options. Uncovering the oncogenic mechanisms could lead to the discovery of potential therapeutic avenues. Here, we demonstrate that the RNA-binding protein ELAVL3 is specifically upregulated in neuroendocrine prostate cancer and that overexpression of ELAVL3 alone is sufficient to induce the neuroendocrine phenotype in prostate adenocarcinoma. Mechanistically, ELAVL3 is transcriptionally regulated by MYCN and subsequently binds to and stabilizes MYCN and RICTOR mRNA. Moreover, ELAVL3 is shown to be released in extracellular vesicles and induce neuroendocrine differentiation of adenocarcinoma cells via an intercellular mechanism. Pharmacological inhibition of ELAVL3 with pyrvinium pamoate, an FDA-approved drug, effectively suppresses tumor growth, reduces metastatic risk, and improves survival in neuroendocrine prostate cancer mouse models. Our results identify ELAVL3 as a critical regulator of neuroendocrine differentiation in prostate cancer and propose a drug repurposing strategy for targeted therapies.

Date: 2023
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DOI: 10.1038/s41467-023-43676-3

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