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. 2025 Feb 10;48(4):100193. doi: 10.1016/j.mocell.2025.100193

The role of transcription factors in prostate cancer progression

Jongeun Lee 1,†, Yoontae Lee 1,⁎
PMCID: PMC11907451  PMID: 39938868

Abstract

Prostate cancer is one of the most common malignancies in men, with most cases initially responding to androgen deprivation therapy. However, a significant number of patients eventually develop castration-resistant prostate cancer, an aggressive form of the disease. Although androgen receptor (AR) pathway inhibitors target AR signaling, and have extended survival in patients with castration-resistant prostate cancer, prolonged treatment can lead to the emergence of neuroendocrine prostate cancer (NEPC), a lethal subtype characterized by the expression of neuroendocrine markers and reduced AR activity. The transition from adenocarcinoma to NEPC is driven by lineage plasticity, wherein cancer cells adopt a neuroendocrine phenotype to evade treatment. Consequently, NEPC patients face poor clinical outcomes and limited effective treatment options. To improve outcomes, it is crucial to understand the molecular mechanisms driving NEPC development. In this review, we highlight the role of transcription factors in this process and explore their potential as therapeutic targets.

Keywords: Castration resistance, Lineage plasticity, Neuroendocrine prostate cancer, Transcription factor

INTRODUCTION

Prostate cancer is one of the most prevalent nonskin cancers diagnosed in men worldwide and remains a significant cause of cancer-related mortality despite advancements in therapeutic interventions (Sung et al., 2021). Approximately 90% to 95% of prostate cancer cases are adenocarcinomas that exhibit strong androgen receptor (AR) expression (Humphrey, 2012). While most cases initially respond well to androgen deprivation therapy (ADT), which inhibits androgen production (Kaipainen et al., 2019), a significant number of patients eventually progress to having castration-resistant prostate cancer (CRPC), an advanced stage that is less responsive to androgen deprivation (Watson et al., 2015). The resurgence of AR signaling in CRPC has led to the development of potent AR pathway inhibitors (ARPIs), such as abiraterone, enzalutamide (ENZ), and apalutamide. These drugs have improved survival rates for patients with advanced prostate cancer (de Bono et al., 2011, Fizazi et al., 2020, Scher et al., 2012). However, prolonged ARPI treatment often induces the development of neuroendocrine prostate cancer (NEPC), a lethal subtype characterized by low or absent AR expression, independence from AR signaling, and acquisition of a neuroendocrine (NE) phenotype (Davies et al., 2018, Vlachostergios et al., 2017, Watson et al., 2015). While de novo NEPC is rare, occurring in <2% of prostate cancer cases at diagnosis, treatment-induced NEPC (t-NEPC) develops in 20% to 25% of patients with CRPC treated with ARPIs (Davies et al., 2018, Zaffuto et al., 2017). This aggressive subtype is associated with poor prognosis, rapid disease progression, and limited treatment options (Aggarwal et al., 2018, Helgstrand et al., 2017). Consequently, identifying the molecular mechanisms that drive NEPC development and leveraging this knowledge to discover novel therapeutic strategies are critical to improving outcomes for NEPC patients.

The development of t-NEPC is believed to be driven by a mechanism of lineage plasticity, a process in which cancer cells transition from an AR-dependent adenocarcinoma phenotype to a NE phenotype (Laudato et al., 2019) (Fig. 1). Lineage plasticity enables cancer cells to evade treatment by adopting alternative phenotypes that are less susceptible to conventional treatments (Beltran et al., 2019a). This phenotypic shift can occur either through transdifferentiation or by dedifferentiation into a stem cell-like state, engaging various molecular pathways (Fig. 1). These include genetic and epigenetic modifications as well as dysregulation of key transcription factors (Davies et al., 2018, Park et al., 2018). Transcription factors such as N-MYC, FOXA1, ASCL1, and ONECUT2 have been identified as critical regulators of the NE phenotype, making them promising therapeutic targets for NEPC (Baca et al., 2021, Beltran et al., 2019b, Rotinen et al., 2018, Tabrizian et al., 2023). This highlights the importance of understanding the transcriptional mechanisms that drive NEPC development, as it could lead to more diverse and effective therapeutic approaches. In this review, we summarize the current understanding of NEPC, with a particular focus on the transcription factors that contribute to its progression.

Fig. 1.

Fig. 1

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Models of neuroendocrine prostate cancer (NEPC) development. NEPC can develop either de novo or through epithelial plasticity of prostate adenocarcinoma cells. De novo NEPC can arise from preexisting neuroendocrine clones under selective pressure from androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs). Following treatment with ADT or ARPIs, AR-positive prostate adenocarcinoma cells often lose AR expression while acquiring NE markers. Epithelial plasticity, including dedifferentiation to stem cell-like state and transdifferentiation from a luminal to an NE cell fate, has emerged as a major model for treatment-induced NEPC (t-NEPC). This transition is thought to be driven by various molecular pathways, genetic and epigenetic alterations, and dysregulation of transcription factors. Pca, prostate cancer; CRPC-Adeno, CRPC adenocarcinoma; CSC, cancer stem cell. Created in BioRender. https://BioRender.com/w11s466.

TRANSCRIPTION FACTORS INVOLVED IN NEPC DEVELOPMENT

Various transcription factors contribute to t-NEPC development, and each of these factors has been studied alongside targeted therapies (Table 1 and Fig. 2). This review highlights transcription factors that induce neuroendocrine differentiation, offering a detailed examination of their roles in NEPC progression.

Table 1.

Transcription factors involved in NEPC development and drugs targeting their functions

Gene name (Symbol) Drug name Drug function Trial no. References
N-MYC Alisertib Aurora A kinase inhibitor NCT01799278 (Phase II) (Beltran et al., 2019b)
FOXA2 Imatinib
Sorafenib
Sunitinib
Cabozantinib		 cKIT inhibitors Sunitinib: NCT00428220 (Han et al., 2022)
ASCL1 JQ-1
ZEN003694
GS-5829		 BET inhibitors ZEN003694: NCT02711956 (Phase I b/ II a)
GS-5829: NCT02607228 (Phase I b/II)		 (Aggarwal et al., 2020, Kim et al., 2021)
ONECUT2 CSRM617
TH-302		 ONECUT2 inhibitor
Hypoxia-activated prodrug		 TH-302: NCT00743379
(Phase I/II)		 (Rotinen et al., 2018)
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Fig. 2.

Fig. 2

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Molecular mechanisms of NEPC-associated transcription factors. Upregulated transcription factors, including ASCL1, N-MYC, BRN2, SOX2, FOXA2, and ONECUT2 (highlighted in red), promote NEPC progression. FOXA1 (highlighted in purple), of which expression is suppressed by ONECUT2, may play a dual role in neuroendocrine differentiation (NED). Reduced expression of transcription factors such as TP53 and REST (highlighted in blue) also contributes to lineage plasticity and NED. The ROR2-ERK-CREB pathway and PHF8 (highlighted in green) induce ASCL1 and FOXA2 expression, respectively, while AURKA (highlighted in green) stabilizes N-MYC. Drugs targeting some of these transcription factors and related pathways, including alisertib, imatinib, sunitinib, CSRM617, and TH-302, are also depicted in the figure. Created in BioRender. https://BioRender.com/k96m394.

N-MYC

N-MYC, encoded by the MYCN gene, is a key transcription factor involved in neural development and plays a critical role in prostate cancer progression, particularly in the development of NEPC. This gene functions as a proto-oncogene, encoding a nuclear phosphoprotein that regulates cell cycle progression, apoptosis, and cellular transformation. It regulates the expression of genes associated with NEPC development, including NSE, SYP, and AR (Beltran et al., 2011). The oncogenic role of N-MYC has been demonstrated through various mouse models. In the Pten+/− mouse model, MYCN overexpression drives the development of aggressive prostate cancers, including NEPC (Dardenne et al., 2016). Additionally, N-MYC promotes resistance to ADT and ENZ through the miR-421/ATM pathway (Yin et al., 2019). The coactivation of N-MYC and AKT1 or ALK leads to the development of NEPC through the Wnt/β-catenin pathway, highlighting the importance of these molecular interactions (Lee et al., 2016, Unno et al., 2021). Furthermore, the combined loss of Rb1 and overexpression of MYCN accelerates the progression of poorly differentiated NE-like tumors and reduces survival in genetically engineered mouse models (Brady et al., 2021).

Targeting the N-MYC and Aurora kinase A (AURKA) pathway presents promising therapeutic potential. The interaction between N-MYC and AURKA is crucial for stabilizing N-MYC in cancer cells (Fig. 2). Clinical trials of alisertib, an AURKA inhibitor, in patients with NEPC have shown that it reduces N-MYC levels and tumor growth (Beltran et al., 2019b, Otto et al., 2009). Additionally, the small-molecule N-MYC inhibitor VPC-70619 exhibits potent antiproliferative activity in N-MYC-positive NEPC cells (Ton et al., 2022).

SOX2

SOX2, a transcription factor belonging to the sex-determining region Y-related high-mobility group box family, plays a critical role in maintaining the pluripotency of embryonic stem cells and regulating neuronal differentiation (Sarkar and Hochedlinger, 2013). It inhibits neuronal differentiation while preserving the stem/progenitor cell characteristics (Graham et al., 2003). In cancer biology, SOX2 promotes tumorigenesis, metastasis, and therapy resistance by driving cancer cell proliferation, invasion, and stemness (Grimm et al., 2020, Novak et al., 2020, Schaefer and Lengerke, 2020). In prostate cancer, SOX2 expression is significantly upregulated in NEPC samples compared to those of prostate adenocarcinoma or CRPC, suggesting its crucial role in NEPC development (Metz et al., 2020). Evidence from both preclinical models and patient samples indicates that SOX2 contributes to cellular lineage plasticity in prostate cancer, facilitating the transition to an NE phenotype following ADT (Mu et al., 2017, Wang et al., 2021).

The expression of SOX2 is regulated by RB1, TP53, and LIN28B (Lovnicki et al., 2020, Mu et al., 2017). Knockdown of both TP53 and RB1 in LNCaP-AR cells leads to a significant upregulation of SOX2 (Fig. 2), which in turn induces the expression of basal and NE markers and contributes to ENZ resistance (Mu et al., 2017). In contrast, knockdown of TP53, RB1, or both in parental LNCaP cells does not induce the expression of SOX2 and other NE markers (Nyquist et al., 2020), suggesting cell-type-specific regulation of SOX2 expression by TP53 and RB1. Therefore, further investigation into the regulatory networks involving SOX2, TP53, and RB1 is essential for developing effective treatment strategies for this aggressive form of prostate cancer.

BRN2

BRN2, encoded by the POU3F2 gene, is a key regulator of neuronal differentiation and plays a pivotal role in promoting the NE phenotype (Balanis et al., 2019). It is highly expressed in ENZ-resistant cell lines exhibiting NE-like characteristics, as well as in human NEPC samples compared to that of CRPC adenocarcinoma (CRPC-Adeno) samples (Beltran et al., 2019a, Bishop et al., 2017). BRN2 expression is inversely correlated with AR activity, as AR directly suppresses BRN2 expression in prostate cancer cells. Furthermore, knockdown of POU3F2 in ENZ-resistant cell lines leads to decreased expression of NE markers and reduced tumor growth, underscoring its critical role in t-NEPC development. BRN2 functions by directly binding to SOX2 and cooperates with it to drive the NE phenotype (Bishop et al., 2017) (Fig. 2).

In addition to BRN2, BRN4, encoded by POU3F4, has also been identified as a regulator of the NE phenotype in prostate cancer cells. Both BRN2 and BRN4 are present in extracellular vesicles (EVs) (Fig. 2), with significantly higher levels detected in the serum of patients with NEPC compared to those with CRPC-Adeno. ENZ treatment induces the release of BRN2 and BRN4 into EVs (Fig. 2), promoting NE differentiation. Elevated levels of these proteins in EVs may serve as noninvasive predictive biomarkers for the early detection of NEPC development (Bhagirath et al., 2019).

TP53

The TP53 gene encodes a tumor suppressor protein that responds to various cellular stresses by regulating the expression of target genes, resulting in outcomes such as cell cycle arrest, DNA repair, or metabolic alterations. Whole-exome sequencing of metastatic prostate cancer samples reveals a greater enrichment of co-occurring RB1 loss and TP53 mutations or deletions in NEPC than in adenocarcinomas (Abida et al., 2019, Aparicio et al., 2016, Beltran et al., 2016). In patients with NEPC, mutations or deletions of TP53 are frequently observed, occurring in 66.7% of cases compared with 31% in patients with CRPC-Adeno. Additionally, concurrent loss of both RB1 and TP53 is found in over 50% of NEPC cases, compared with approximately 14% of CRPC-Adeno cases, suggesting their synergistic role in promoting NEPC development (Beltran et al., 2016). In mouse models, deletion of both Rb1 and Trp53 in the prostate luminal epithelial cells leads to aggressive, highly metastatic prostate cancer that is resistant to ADT and displays NE differentiation (Zhou et al., 2006).

The roles of PTEN, TP53, and RB1 in prostate cancer have been further explored using genetic models. While PTEN loss initiates primary prostate tumorigenesis, the loss of TP53 or RB1 alone does not initiate tumorigenesis but accelerates prostate cancer progression and metastasis when combined with PTEN loss (Chen et al., 2005, Ku et al., 2017, Navone et al., 1999, Zhou et al., 2006). Moreover, coinactivation of TP53 and PTEN in mice results in resistance to ARPIs, such as abiraterone, and induces a pronounced NE phenotype. Similarly, RB1 loss facilitates metastasis and lineage plasticity in PTEN-null models, with additional TP53 loss exacerbating resistance to AR-targeted therapies (Ku et al., 2017). Collectively, these mutations promote the conversion of prostate adenocarcinoma into NEPC, with TP53 and RB1 playing critical roles in suppressing this transformation under normal conditions.

REST

The repressor element 1-silencing transcription factor (REST) is a key transcriptional repressor that controls neuronal gene expression by binding to the RE-1 site, thereby preventing neuronal differentiation in non-neuronal cells (Schoenherr and Anderson, 1995). It achieves this by recruiting corepressors such as REST corepressor and histone deacetylases (Ballas et al., 2005). REST is universally expressed in non-neuronal tissues, including prostate adenocarcinoma, but its expression is markedly reduced in neuronal cells, stem cells, and NEPC samples (Zhang et al., 2015).

Proteomic data from patient-derived xenografts (PDXs) and chromatin immunoprecipitation-sequencing analysis of REST-binding regions have confirmed that REST downregulation plays a significant role in promoting NE marker expression in NEPC cells (Flores-Morales et al., 2019). Silencing REST expression in LNCaP cells leads to the upregulation of NE markers, even in the presence of active androgen signaling (Chen et al., 2017, Svensson et al., 2014). Additionally, treatment with ARPIs can induce the expression of SRRM4, an RNA splicing factor that generates a loss-of-function REST4 isoform (Fig. 2). This isoform lacks the transcriptional repressor domain of full-length REST, contributing to REST inactivation in NEPC cells (Li et al., 2017). Although REST downregulation is a critical step in facilitating NE differentiation in prostate cancer, the precise molecular mechanisms underlying its reduction in NEPC cells remain unclear.

FOXA1

Forkhead box A (FOXA) family proteins act as pioneer factors, enabling the remodeling of compact chromatin structures. FOXA1 plays a critical role in the progression and drug resistance of prostate cancer (Gerhardt et al., 2012). As a coactivator for AR, FOXA1 facilitates AR recruitment to enhancer regions of key genes involved in prostate cancer development, such as UBE2C (Beltran et al., 2020, Sahu et al., 2011, Wang et al., 2009). In AR-low prostate cancer subgroups, high FOXA1 expression is associated with shorter relapse-free survival, a correlation not observed in AR-high subgroups (Gerhardt et al., 2012). FOXA1 mutations are prevalent in prostate cancer, appearing in approximately 9% of primary and 13% of metastatic CRPC-Adeno cases (Adams et al., 2019). These mutations are also frequent in NEPC. Notably, FOXA1 mutations can occur in both coding and noncoding regions, with noncoding mutations influencing FOXA1 target gene expression. In fact, more than 34% of patients with metastatic CRPC have both coding and noncoding FOXA1 mutations, likely contributing to disease progression (Parolia et al., 2019, Zhou et al., 2020). Additionally, mutations in specific FOXA1 forkhead domain hotspots, such as Wing2 and the conserved DNA-contact residue R219, can inhibit luminal differentiation and activate NE transcription programs, promoting lineage plasticity (Adams et al., 2019).

The role of FOXA1 in NEPC is complex (Fig. 2). While some studies report FOXA1 downregulation in NEPC patients and LNCaP-derived NEPC xenografts (Kim et al., 2017), others highlight its high expression in NEPC models, such as LuCaP PDXs and NEPC cell lines (Baca et al., 2021, Gerhardt et al., 2012). In NE-like PC-3 cells, FOXA1 overexpression decreases the expression of ENO2, an NE marker, and induces loss of NE characteristics by inhibiting IL-8 expression, thereby blocking the MAPK/ERK pathway (Kim et al., 2017). Conversely, FOXA1 knockdown in NEPC cell line reduces the expression of NEPC markers, including SYP and CHGA, indicating that FOXA1 is an essential transcription factor in NEPC (Baca et al., 2021). This dual role of FOXA1, both promoting and inhibiting NE differentiation depending on context, suggests the need for further research to fully understand its function in NEPC.

FOXA2

FOXA2, another critical member of the FOXA family proteins, is significantly upregulated in NEPC cell lines, PDXs, and patient tissues (Mirosevich et al., 2006, Park et al., 2017). The histone demethylase PHF8 drives the transcriptional upregulation of FOXA2 expression (Fig. 2), contributing to NEPC development in the TRAMP mouse model (Liu et al., 2021). In addition, FOXA2 serves as a specific tissue marker for NEPC, with a sensitivity of 75% and a specificity of over 95%, potentially making it a more accurate molecular indicator than other markers for identifying patients with NEPC (Park et al., 2017).

Functionally, FOXA2 is involved in prostate cancer metastasis and the development of NE phenotypes (Cheng and Yu, 2019, Connelly et al., 2020). FOXA2-knockdown PC-3 cells generate fewer bone lesions following intratibial injection compared with control cells, suggesting its potential role in bone metastasis in NEPC (Connelly et al., 2020). In the Siah2-null TRAMP mouse model, FOXA2 is essential for the hypoxia-induced NE phenotype by upregulating the expression of Hes6, Sox9, and Jmjd1a (Qi et al., 2010). Additionally, in the TPPRC mouse model, FOXA2 expression is significantly upregulated in response to ADT, driving the transition from adenocarcinoma to NE lineage. Moreover, FOXA2 directly regulates the KIT pathway (Fig. 2), which is activated in NEPC cells (Han et al., 2022). FOXA2 also interacts with JUN and promotes transcriptional reprogramming of AP-1 in lineage-plastic cancer cells, thereby facilitating cell state transitions to multiple lineages (Wang et al., 2024). Collectively, these studies establish FOXA2 as a key regulator in the development of NEPC.

ASCL1

Achaete-scute homolog 1 (ASCL1) is a lineage-determining transcription factor that plays a crucial role in lineage plasticity, neural transcriptional programs, and the acquisition of treatment resistance and NE phenotypes in both prostate and lung cancers (Augustyn et al., 2014, Balanis et al., 2019, Nouruzi et al., 2022). ASCL1 expression is significantly elevated in NEPC cells compared with CRPC-Adeno and primary prostate cancer cells. Overexpression of ASCL1 in LNCaP cells drives the NE phenotype by inducing FOXA1 to bind to NE regulatory elements through histone modification at the enhancer sites (Baca et al., 2021). Interestingly, subtypes of t-NEPC with distinct genetic and epigenetic characteristics can be classified based on the expression patterns of ASCL1 and NeuroD1 in various NEPC PDX models and cell lines (Cejas et al., 2021).

Recent studies have identified mechanisms regulating ASCL1 expression. Chromatin remodeling induced by ARPIs has been linked to increased ASCL1 expression and activity (Nouruzi et al., 2022). ROR2, identified as the most upregulated receptor tyrosine kinase following AR pathway inhibition, promotes lineage plasticity by enhancing stem cell-like and neuronal networks. Mechanistically, ROR2 activates the ERK/CREB signaling pathway to regulate ASCL1 expression, which in turn influences the lineage commitment to NEPC, further reinforcing its role in NE transdifferentiation (Tabrizian et al., 2023) (Fig. 2).

ONECUT2

One cut domain family member 2 (ONECUT2), which activates the transcription of genes associated with liver function, such as HNF3B, has emerged as a potential master regulator of NE cancers, including NEPC, small-cell lung cancer, and neuroblastoma, based on clinical dataset analyses (Guo et al., 2019, Rotinen et al., 2018). ONECUT2 expression is significantly elevated in patients with NEPC, and its overexpression promotes the NE phenotype and enhances NEPC cell proliferation. Mechanistically, the upregulation of ONECUT2 in NEPC cells is driven by REST loss-of-function (Fig. 2), contributing to NE transdifferentiation in prostate cancer. Additionally, ONECUT2 represses AR and FOXA1, further enhancing the NE phenotype (Rotinen et al., 2018) (Fig. 2).

ONECUT2 has been identified as a key regulator of hypoxia signaling, particularly through the activation of SMAD3, which in turn enhances HIF-1α chromatin binding (Guo et al., 2019). Since hypoxia is associated with prostate cancer progression and the induction of NE differentiation, targeting ONECUT2-mediated hypoxia signaling could be a promising therapeutic strategy (Guo et al., 2019, O'Reilly et al., 2019). The hypoxia-activated prodrug TH-302 has shown efficacy in inhibiting tumor growth in both PC-3 xenograft and NEPC PDX models (Guo et al., 2019) (Fig. 2). Furthermore, treatment with CSRM617, a small- molecule inhibitor targeting ONECUT2, significantly reduces prostate cancer tumor growth and metastasis in vivo (Rotinen et al., 2018) (Fig. 2). Collectively, these findings suggest that targeting ONECUT2 could represent a novel therapeutic strategy not only for metastatic prostate cancer, such as NEPC, but also for broader NE cancers.

CONCLUSION AND PERSPECTIVES

One of the most significant challenges in prostate cancer treatment is managing CRPC and its more aggressive variant, NEPC. Progress in developing effective treatments for NEPC has been slow, primarily due to patients often undergoing prolonged ADT or ARPI treatment. This extended treatment can induce lineage plasticity, resulting in a transition from adenocarcinoma to NE phenotypes. Consequently, clinical outcomes for NEPC patients remain disheartening, with limited therapeutic options available. There is an urgent need for research focused on discovering novel therapeutic targets and for clinical trials aimed at elucidating the mechanisms driving NEPC development. Many studies are dedicated to uncovering the molecular mechanisms that drive NE differentiation, with the aim of leveraging these insights to enhance patient survival and treatment efficacy. This review specifically highlights the role of transcription factors in NEPC and discusses promising therapeutic targets that could help reduce mortality associated with this aggressive cancer.

Furthermore, the treatment-induced transition to NE cancer is not exclusive to prostate cancer but occurs in a variety of other NE cancers, including neuroblastoma, small-cell lung cancer, and pancreatic neuroendocrine tumors. As a result, drugs developed for these other NE cancers may have potential as agents for targeting NE differentiation in prostate cancer. Additionally, therapeutic targets identified through NEPC research could hold significant promise for treating a broader spectrum of NE cancers.

FUNDING AND SUPPORT

This study was supported by National Research Foundation of Korea grants funded by the Korean government (2021R1A6A1A10042944, 2022M3E5F2018020, RS-2023-00260454, and RS-2024-00336114) and a Korea Basic Science Institute (National Research Facilities and Equipment Center) grant funded by the Ministry of Education (2021R1A6C101A390). JL was supported by a Global PhD Fellowship (NRF-2018H1A2A1059794).

AUTHOR CONTRIBUTIONS

JL and YL wrote the paper. YL supervised the paper and provided feedback.

CRediT AUTHORSHIP CONTRIBUTION STATEMENT

Lee Yoontae: Writing – review & editing, Writing – original draft, Supervision, Conceptualization. Lee Jongeun: Conceptualization, Writing – original draft.

DECLARATION OF COMPETING INTERESTS

There are no competing interests.

ORCID

Jongeun Lee: https://orcid.org/0000-0003-4668-2329

Yoontae Lee: https://orcid.org/0000-0002-6810-3087

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