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

Author:

Ji Yiyi,Zhang WeiweiORCID,Shen Kai,Su Ruopeng,Liu Xinyu,Ma Zehua,Liu Bo,Hu Cong,Xue Yizheng,Xin Zhixiang,Yang Yi,Li Ang,Jiang Zhou,Jing Na,Zhu Helen HeORCID,Dong Liang,Zhu Yinjie,Dong Baijun,Pan Jiahua,Wang QiORCID,Xue Wei

Abstract

AbstractNeuroendocrine 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.

Funder

National Natural Science Foundation of China

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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