ETV5 reduces androgen receptor expression and induces neural stem-like properties during neuroendocrine prostate cancer development

• 成果类型: Article
• 署名作者: Lee, Jongeun; Park, Jiho; Hur, Yunjung; Um, Dahun; Choi, Hyung-Seok; Park, Joonyoung; Kim, Yewon; Lee, Jeon-Soo; Choi, Kyuha; Kim, Eunjeong; Park, Young Bin; Choi, Jae-Mun; Kim, Tae-Kyung; Lee, Yoontae
• 署名单位: Pohang University of Science & Technology (POSTECH); Kyungpook National University (KNU); Chungnam National University; Korea University; Yonsei University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8996
• DOI: 10.1073/pnas.2420313122
• 发表日期: 2025-03-25
• 关键词: transcription factors; increased survival; cells; castration; resistance; ACID; enzalutamide; phenotype; carcinoma

摘要

Neuroendocrine prostate cancer (NEPC), an aggressive subtype induced by hormone therapy, lacks effective treatments. This study explored the role of E26 transformation-specific variant 5 (ETV5) in NEPC development. Analysis of multiple prostate cancer datasets revealed that NEPC is characterized by significantly elevated ETV5 expression compared to other subtypes. ETV5 expression increased progressively under hormone therapy through epigenetic modifications. ETV5 induced neural stem-like features in prostate cancer cells and facilitated their differentiation into NEPC under hormone treatment conditions, both in vitro and in vivo. Our molecular mechanistic study identified PBX3 and TLL1 as target genes of ETV5 that contribute to ETV5 overexpression-induced castration resistance and stemness. Notably, obeticholic acid, identified as an ETV5 inhibitor in this study, exhibited promising efficacy in suppressing NEPC development. This study highlights ETV5 as a key transcription factor that facilitates NEPC development and underscores its potential as a therapeutic target for this aggressive cancer subtype.