ETV5 Reduces Androgen Receptor Expression and Induces Neural Stem–Like Properties During Neuroendocrine Prostate Cancer Development

Sep 23, 2026

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype driven by hormone therapy and lacks effective treatments. This study evaluates the role of E26 transformation-specific variant 5 (ETV5) in NEPC development. Multi-dataset analysis shows elevated ETV5 expression in NEPC that increases under hormone therapy via epigenetic modifications. ETV5 promotes neural stem–like features and differentiation into NEPC in vitro and in vivo, identifying PBX3 and TLL1 as target genes supporting castration resistance and stemness. Obeticholic acid suppresses NEPC development by inhibiting ETV5 activity.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages10

Reading Time25 min

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Research summary

RESEARCH ARTICLE MEDICAL SCIENCES ETV5 reduces androgen receptor expression and induces neural stem–like properties during neuroendocrine prostate cancer development Jongeun Leea , Jiho Parka, Yunjung Hura , Dahun Uma, Hyung-Seok Choia , Joonyoung Parka , Yewon Kima , Jeon-Soo Leea, Kyuha Choia , Eunjeong Kimb, Young Bin Parkc , Jae-Mun Choic,d,e, Tae-Kyung Kima, and Yoontae Leea,f,1 Affiliations are included on p. 10. Edited by Myles Brown, Dana-Farber Cancer Institute, Boston, MA; received October 3, 2024; accepted February 18, 2025 Neuroendocrine prostate cancer (NEPC), an aggressive subtype induced by hormone therapy, lacks effective treatments. This study explored the role ofE26 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. neuroendocrine prostate cancer | androgen receptor | castration resistance | obeticholic acid | ETV5 Prostate cancer development relies on androgen receptor (AR) signaling pathways. Consequently, therapeutic strategies have been developed to target androgen production and AR signaling. Standard hormone therapies, such as androgen deprivation therapy (ADT) andAR pathway inhibitors [e.g., enzalutamide (ENZ)], have demonstrated efficacy in impeding cancer progression and improving patient survival (1–4). However, resistance to these therapies commonly emerges, often because of increased AR expression or the appearance of constitutively active AR variants, such as AR-V7, consequently resulting in castration-resistant prostate cancer (CRPC) (2) . Prolonged exposure to hormone therapies can also lead to the emergence of neuroendocrine prostate cancer (NEPC), a distinct subtype of CRPC characterized by lineage plasticity toward AR-negative neural traits (5, 6). These therapy-induced NEPC (t-NEPC) cells exhibit diminished AR expression and signaling, along with elevated expression of neuroendocrine markers, such as CHGA, CHGB, SYP, and NCAM1, as well as increased expression of neuronal stem/progenitor cell (NSPC) markers, such as SOX2 and CD44 (7). The development oft-NEPC is driven by a complex interplay between genetic and epigenetic alterations (8, 9), including the loss-of-function of tumor suppressor genes such as PTEN, TP53, and RB1 (2, 10, 11), and activation of transcription factors, such as SOX2, ASCL1, MYCN, ONECUT2, and FOXA1 (11–16) . In addition, epigenetic regulatory mechanisms involving EZH2 and chromatin-remodeling complexes play significant roles in treatment-induced lineage plasticity (17, 18). Notably, AR expression has been closely linked to lineage plasticity toward stem cell traits (19–22) . Despite the identification of numerous factors that influence AR signaling, the molecular mechanisms underlying decreased AR expression after therapy remain inadequately understood. The E26 transformation-specific (ETS) protein family is one of the largest evolutionarily conserved transcription factor families (23, 24) . Proteins in this family share a conserved winged helix–turn–helix DNA binding domain (ETS domain), which recognizes unique DNA sequences containing GGAA/T (24) . E

FAQs

What problem does the study address in neuroendocrine prostate cancer?

NEPC is an aggressive subtype that arises during hormone therapy and currently has limited effective treatments.

How does ETV5 relate to NEPC progression during hormone therapy?

ETV5 expression becomes elevated and increases progressively under hormone therapy, driving neural stem–like features and facilitating differentiation into NEPC.

What genes and therapeutic approach does the study identify?

PBX3 and TLL1 are reported as ETV5 target genes contributing to castration resistance and stemness, and obeticholic acid is shown to inhibit ETV5 and suppress NEPC development.

Sep 23, 2026

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