The RNA helicase DDX17 enhances androgen receptor stability by interacting with the E3 ubiquitin ligase SPOP in prostate cancer

Introduction

Prostate cancer (PCa) originates in the epithelial tissues of the prostate gland and is influenced by multiple factors (1). Despite improvements in early detection and treatment methods, many patients still receive their initial diagnosis at advanced stages of the disease (2). This is often due to the lack of early symptoms and the aggressive nature of some PCa subtypes. Conventional treatments like surgery, radiation therapy, and androgen deprivation therapy (ADT) have traditionally been fundamental in managing PCa (3,4). However, these methods often fall short in effectively addressing advanced or metastatic cases and can lead to significant side effects (5-7). Additionally, PCa cells may develop resistance to androgen deprivation by significantly increasing androgen receptor (AR) expression over time (6).

Recent advancements in molecular biology have dramatically transformed the field of cancer treatment (8), providing new avenues for targeted therapies (9,10). For instance, the use of poly (ADP-ribose) polymerase (PARP) inhibitors like olaparib has proven effective in treating metastatic castration-resistant PCa with mutations in homologous recombination repair genes (11). Furthermore, progress in immunotherapy, particularly the development of immune checkpoint inhibitors, has shown promising results in PCa treatment (12,13).

Despite these advancements, there remains an urgent need to identify and validate novel molecular targets to enhance therapeutic outcomes for patients with PCa. A key area of interest is the AR, a principal driver of PCa development and progression (14). The AR signaling axis is crucial to PCa biology, and its activation supports the growth and survival of PCa cells (15-17).

AR is a transcription factor (18) that regulates genes essential for prostate cell growth and survival, and it stimulates tumor growth in PCa by facilitating cell proliferation (14). Initially, PCa relies on androgens for growth; however, as the disease evolves into castration-resistant prostate cancer (CRPC), AR signaling may become deregulated, enabling tumors to grow even under low androgen conditions. Treatment options include ADT, anti-androgens that block AR activity, and inhibitors targeting AR signaling. Recent approaches aim to target mutant forms of AR and integrate AR-targeted therapies with other treatments to mitigate resistance and improve outcomes for patients.

DDX17, also known as RNA helicase p72, is pivotal in regulating gene expression through transcription, RNA splicing, and the modification of RNA structures (19-21). The role of this enzyme in various cellular processes has associated DDX17 with multiple cancer types, often playing a significant part in tumorigenesis and cancer progression (22,23).

In our study on PCa, we have discovered distinct roles of DDX17 that set it apart from its functions in other cancers, providing fresh perspectives on its involvement in PCa. A key finding from our research is the interaction between DDX17 and the E3 ubiquitin ligase, SPOP, which is frequently mutated in PCa and endometrial cancer (24). Our findings revealed that DDX17 directly interacts with SPOP, inhibiting its ability to ubiquitinate and degrade AR. This action results in the stabilization of AR, a critical factor in PCa progression. This interaction contrasts with the typical role of DDX17 in other cancers, where it primarily influences gene expression and RNA processing. In PCa, DDX17 specifically modulates AR at the post-translational level by preventing SPOP-mediated ubiquitination. This unique DDX17–SPOP–AR axis unveils a specific regulatory mechanism in PCa, where DDX17 can enhance AR signaling and foster tumor growth, offering novel pathways for targeted therapeutic strategies.

The discovery of the DDX17-SPOP-AR axis as a critical pathway in PCa progression opens new avenues for targeted therapy. Our findings indicate that developing inhibitors that either disrupt the DDX17-SPOP interaction or increase SPOP ubiquitin ligase activity could specifically destabilize AR in PCa cells. This approach could decrease tumor growth and enhance the effectiveness of existing treatments. Such therapeutic strategy, uniquely aligned with the molecular characteristics of PCa, presents a novel method not previously explored in the context of other cancers.

The identification of the DDX17-SPOP-AR axis marks a substantial breakthrough in elucidating the molecular mechanisms driving PCa. This discovery sheds light on how AR stabilization influences PCa progression and opens up promising possibilities for therapeutic intervention. Moreover, by targeting this specific pathway, novel treatments can be developed that directly interfere with these molecular interactions. Such targeted therapies have the potential to significantly improve treatment efficacy for PCa patients, offering a new avenue for combating this disease more effectively and perhaps reducing the incidence of resistance observed in current treatment modalities. We present this article in accordance with the MDAR reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-167/rc).

Methods

Gene expression analysis

Gene expression data and clinical information for PCa patients were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. RNA sequencing data from TCGA were processed using the EdgeR package in R. Data from the GEO database underwent log2 transformation and were normalized through quantile normalization. Differential expression analysis was performed using the limma package in the R software. The TCGA dataset was also utilized for conducting survival analysis. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Cell culture

Human PCa cell lines (C4-2 and LNCaP) purchased from Procell (Wuhan, China) were used in this study. These cells were cultured in RPMI-1640 medium from Lonza (Basel, Switzerland), enriched with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin, and maintained under a 5% CO₂ atmosphere at 37 ℃. All cell lines underwent authentication via short tandem repeat (STR) profiling, and were confirmed to be free from mycoplasma contamination.

Cell transfection

Small interfering RNAs (siRNAs) designed to target DDX17 or SPOP (si-DDX17 or si-SPOP) were obtained from Tsingke (Beijing, China). Non-targeted siRNAs served as negative controls (si-NC).

Quantitative real-time polymerase chain reaction (qRT-PCR)

Total RNA was isolated using TRIzol reagent, followed by cDNA synthesis using HiScript III RT SuperMix (Vazyme, Nanjing, China). The qRT-PCR was performed using SYBR (Synthetic Yeast Binding Reagent) Green Taq Mix (Vazyme). Relative expression levels were determined using the 2^–ΔΔCT method with GAPDH as an internal reference.

Western blotting

Total protein was extracted using RIPA (Radio Immuno Precipitation Assay) buffer, which included a cocktail of protease and phosphatase inhibitors (Beyotime, Beijing, China). Protein concentrations were measured using the bicinchoninic acid (BCA) assay. The proteins were then separated by 10% sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and subsequently transferred onto nitrocellulose membranes. These membranes were incubated overnight with primary antibodies at 4 ℃, followed by a 2-hour incubation with secondary antibodies (1:5,000) from Abcam at 37 ℃. Protein detection was carried out using the enhanced chemiluminescence (ECL) Reagent Kit (Invitrogen, Carlsbad, CA, USA).

Transwell assay

For the cell invasion assays, transwell plates were utilized. The bottom of the upper chamber of these plates was pre-coated with 60 µL of Matrigel, which was diluted with serum-free medium. Approximately 1×10⁵ C4-2 and LNCaP-EZ25 cells were seeded into the upper chambers, with 500 µL of complete medium in the lower chambers. After 24 hours, cells that had invaded the lower compartment were stained with crystal violet and counted using a microscope.

Co-immunoprecipitation (Co-IP) assay

Cells were lysed using 500 μL of Co-IP buffer, which contained 50 mM Tris (pH 7.5), 150 mM NaCl, 5 mM EDTA, 1–2% Nonidet P-40, and a protease inhibitor cocktail. Proteins were separated using a Bolt 10% gel and incubated with 100 µL of protein A+G agarose beads at 4 ℃ for 4 hours. After the incubation, the beads were washed and the protein complexes were detected using Western blotting.

Cell counting kit-8 (CCK-8) assay

C4-2 and LNCaP-EZ25 cells were plated at a density of 2,000 cells per well in a 96-well plate and incubated at 37 ℃. After culturing, 10 microliters of CCK-8 solution (APExBIO Technology LLC, USA) were added to each well and incubated for 4 hours. The absorbance at 450 nm was then measured using a microplate reader. Each assay was performed in triplicate to generate a cell growth curve.

Statistical analysis

Kaplan-Meier curves for overall survival were created using GraphPad Prism software. Data were shown as mean ± standard deviation and analyzed with the Student’s t-test. Differences in overall survival based on gene expression levels were evaluated using the log-rank test. A multivariate Cox proportional hazards model was applied to identify predictors of overall survival. A P value of less than 0.05 was considered statistically significant. All experiments were conducted in triplicate.

Results

Upregulation of DDX17 is associated with poor prognosis in patients with PCa

We conducted a thorough examination of DDX17 expression across various cancers, specifically focusing on PCa, using extensive data from the TCGA database (Figure 1A). Our findings indicated a significant increase in DDX17 levels in PCa tissues compared to normal prostate tissues (Figure 1B,1C). As shown in Figure S1A, DDX17 exhibited low expression levels in normal prostate tissues, whereas its expression was significantly upregulated in PCa tissues. Additionally, DDX17 expression was significantly elevated in metastatic PCa (N1) compared to both non-metastatic (N0) and normal prostate tissues (Figure 1D). DDX17 expression progressively increased with higher Gleason scores (GS6 to GS8, P<0.05, Figure 1E). Notably, we observed a modest reduction in DDX17 expression at GS9, prompting the hypothesis that DDX17 levels may decrease during late-stage prostate carcinogenesis. Clinically, elevated DDX17 expression correlated with poorer overall survival, establishing its prognostic value in PCa (Figure 1F). Overall, our findings indicate that DDX17 could be a valuable biomarker for both the diagnosis and prognosis of PCa, with high expression levels associated with worse outcomes, thereby underscoring its potential as a prognostic marker in PCa.

Figure 1 DDX17 upregulation is associated with adverse prognosis in patients with prostate cancer. (A) DDX17 expression levels across various types of tumors and their corresponding normal tissues. (B,C) DDX17 expression levels in normal and tumor tissues in PRAD. (D) DDX17 expression levels show variations across normal prostate tissues. (E) DDX17 expression levels across prostate cancer stratified by Gleason score. (F) The impact of DDX17 expression levels on the overall survival of patients. *, P<0.05; **, P<0.01; ***, P<0.001. PRAD, prostate cancer; TCGA, The Cancer Genome Atlas.

DDX17 promotes the growth of PCa cells

In our earlier study, we established an enzalutamide-resistant PCa cell line, termed LNCaP-EZ25, by continuously treating LNCaP cells, which are at the Hormone-sensitive prostate cancer (HSPC)-stage of PCa, with enzalutamide. To establish a baseline expression profile of DDX17, we performed Western blot analysis across four PCa cell lines (C4-2, LNCaP-EZ25, PC3, and DU145). As shown in Figure S1B, DDX17 protein levels were significantly higher in C4-2 and LNCaP cells compared to PC3 and DU145, which exhibited relatively low expression. Based on these findings, we selected C4-2 and LNCaP-EZ25 for subsequent functional studies, as their elevated DDX17 expression provided a biologically relevant model to investigate the potential role of DDX17 in PCa progression (Figure S1C).To explore the impact of DDX17 on PCa development and progression, we employed siRNA technology to suppress DDX17 expression in the C4-2 and LNCaP-EZ25 PCa cell lines (Figure 2A,2B). We then conducted CCK-8 (Figure 2C,2D) and transwell assays (Figure 2E,2F) to assess the effects of DDX17 silencing on cellular proliferation and invasion. The results show that DDX17 knockdown significantly diminished both the proliferation and invasion abilities of the PCa cells.

Figure 2 DDX17 promotes growth in prostate cancer cells. (A,B) DDX17 knockdown efficiency graph. (C,D) The proliferation capacity of LNCaP-EZ25 and C4-2 prostate cancer cell lines after DDX17 knockdown (SiDDX17) compared to that of the negative control. (E,F) Invasion assay of prostate cancer cell lines (LNCaP-EZ25 and C4-2) following DDX17 knockdown. Invading cells were fixed and stained with crystal violet. Magnification: 100×. **, P<0.01; ***, P<0.001; ****, P<0.0001. NC, negative control; OD, optical density.

Interaction between DDX17 and AR

First, we performed a Co-IP experiment to confirm the direct interaction between AR and DDX17 (Figure 3A,3B and Figure S1D,S1E). After silencing DDX17, we measured the expression levels of AR and its downstream target, KLK3. The results depicted in Figure 3C,3D show that while DDX17 silencing did not alter AR mRNA levels, it significantly decreased the mRNA levels of KLK3. Thus, we inferred that DDX17 did not influence the transcriptional levels of AR. Instead, DDX17 indirectly affected the expression of genes downstream of AR rather than directly participating in the transcriptional regulation of AR.

Figure 3 DDX17 regulates AR protein stability and prevents its degradation. (A,B) The interaction between DDX17 and AR in a Co-IP experiment. (C,D) Impact of DDX17 knockdown on the mRNA expression levels of AR and its downstream genes. (E-H) The impact of DDX17 knockdown on the protein expression levels of AR and its downstream. (I,J) CETSA on C4-2 and LNCaP-EZ25 cells following DDX17 silencing. (K,L) Half-life experiment in C4-2 and LNCaP-EZ25 cells following DDX17 silencing. (M) Ubiquitination levels of AR following DDX17 silencing. ns, not significant; **, P<0.01; ***, P<0.001. AR, androgen receptor; CETSA, cellular thermal shift assay; Co-IP, co-immunoprecipitation; NC, negative control.

Further analysis revealed significant reductions in the protein levels of AR and KLK3 following DDX17 knockdown (Figure 3E-3H). These observations indicate that DDX17 might regulate either the synthesis or the degradation of the AR protein.

Our results from the cellular thermal shift assay (CETSA) indicated that DDX17 is crucial for maintaining the thermal stability of the AR protein. In cells where DDX17 was silenced, there was a notable decrease in AR protein stability at elevated temperatures (46 ℃ and higher). Observations in drug-resistant cell lines corroborated that DDX17 is critical for the stability of the AR protein (Figure 3I,3J).

Additionally, half-life experiments conducted on C4-2 and LNCaP-EZ25 cells revealed that AR protein levels declined significantly over time following DDX17 silencing, with levels falling below 50% within 8 hours. Conversely, AR protein levels remained stable in the negative control group. These outcomes (Figure 3K,3L) affirm that DDX17 is crucial for maintaining AR protein stability and inhibiting its degradation. Further ubiquitination assays indicated that DDX17 can regulate AR protein stability via the ubiquitin-proteasome pathway (Figure 3M).

DDX17 affects AR protein ubiquitination and degradation through SPOP

Through analysis of extensive samples from public databases, we discovered a notable positive correlation between the expression levels of DDX17 and SPOP (Figure 4A). Structurally, SPOP features a POZ (Pox virus and Zinc finger) domain, which facilitates protein-protein interactions and plays a role in regulatory processes, including protein interactions and degradation within cells, showing functional similarities. Prior research has established that SPOP directly affects the ubiquitination of the AR protein. We hypothesized that DDX17 indirectly regulates the AR protein through its interaction with SPOP.

Figure 4 DDX17 affects AR protein ubiquitination and degradation via SPOP. (A) DDX17 expression and SPOP are significantly positively correlated. (B,C) The interaction between DDX17 and SPOP in Co-IP experiment. (D,E) The effect of simultaneous silencing of DDX17 and SPOP on AR mRNA levels. (F,G) The effect of simultaneous silencing of DDX17 and SPOP on AR protein levels. (H) The simultaneous silencing of DDX17 and SPOP and its effect on the overall ubiquitin levels. (I,J) Proteasome and lysosomal inhibitors are given separate levels. AR, androgen receptor; Co-IP, co-immunoprecipitation; NC, negative control; PRAD, prostate cancer; TCGA, The Cancer Genome Atlas.

To confirm the interaction between DDX17 and SPOP and its effect on AR protein stability, we performed Co-IP experiments (Figure 4B,4C). These experiments verified the physical interaction between DDX17 and SPOP. This finding strengthened our resolve to concentrate on SPOP in subsequent studies, investigating whether DDX17 influences AR protein degradation through the SPOP pathway.

Subsequently, we performed a double-knockdown experiment where both DDX17 and SPOP were simultaneously silenced to assess changes in AR mRNA levels. The findings revealed that the silencing of either DDX17 or SPOP did not affect AR mRNA expression (Figure 4D,4E). We then conducted western blot analyses (Figure 4F,4G) to examine the specific effects of gene silencing on AR protein levels, discovering that DDX17 and SPOP synergistically operate within the same protein degradation pathway (Figure 4H). This suggests that DDX17 can regulate AR degradation through a mechanism involving SPOP, with SPOP acting as a crucial modulator. Further analysis of protein ubiquitination levels supported the idea that DDX17 and SPOP regulate protein stability and degradation primarily through the ubiquitin-proteasome pathway.

Finally, using the lysosomal inhibitor bafilomycin A1 (Figure 4I,4J), we established that DDX17-mediated AR degradation primarily occurs through the ubiquitin-proteasome pathway. Blocking the proteasomal pathway with MG132 resulted in stable AR levels, despite the silencing of DDX17, indicating that MG132 effectively inhibited AR degradation, leading to its accumulation. On the other hand, treatment with bafilomycin A1 did not significantly impact AR levels, which remained markedly reduced following DDX17 silencing compared to the control group. These results confirmed that DDX17 can predominantly block AR degradation via the ubiquitin-proteasome pathway.

Discussion

PCa is a prevalent cancer among men, heavily influenced by androgen signaling. The initial approach to treating PCa typically involves ADT, which reduces systemic androgen levels and curtails AR activity to curb tumor growth. While ADT is initially successful for many patients, numerous cases eventually progress to CRPC, a condition where PCa advances despite ADT. CRPC cells might activate alternative growth and survival pathways, enabling tumor progression irrespective of AR signaling. AR, a nuclear transcription factor, plays a pivotal role in the development and progression of PCa. It regulates a network of genes that are crucial for cell proliferation and survival by binding to androgens, such as testosterone (T) or dihydrotestosterone (DHT), thus promoting tumor growth and progression.

Our study revealed the role of the RNA helicase DDX17 in regulating AR stability in PCa. Previous studies have highlighted the intricate interactions between AR and various E3 ubiquitin ligases, which are essential for modulating AR stability and function. Among these, SPOP is particularly significant due to its involvement in AR ubiquitination and degradation. Notably, SPOP mutations are frequently detected in PCa, leading to enhanced AR activity and resistance to ADT. Additionally, other E3 ligases, such as MDM2, SKP2, and STUB1, contribute to AR regulation by mediating its ubiquitination, thereby influencing its stability and transcriptional activity. These findings emphasize the complexity of AR regulation and underscore the need to better understand these mechanisms to develop strategies for overcoming treatment resistance in PCa. However, the specific role of DDX17 in this process has remained largely unexplored. Our findings suggest that DDX17 plays a novel and critical role within this regulatory network.

DDX17, which plays a crucial role in various aspects of RNA metabolism such as splicing, transcription, and translation, has been linked to multiple cancers, including breast, colon, liver, lung, and pancreatic cancers. In breast cancer, DDX17 serves as a transcriptional co-activator for estrogen receptor α (ERα), affecting tumor growth and survival (25). In colon cancer, it promotes oncogene expression and inhibits tumor suppressor gene activity (26), whereas in hepatocellular carcinoma, it promotes metastasis through the activation of MYC transcription (27). Its role in lung cancer includes disrupting the E-cadherin/β-catenin complex, thereby facilitating β-catenin’s nuclear translocation and contributing to drug resistance (28). In pancreatic ductal adenocarcinoma (PDAC), DDX17 increases splicing activity linked to tumor malignancy, highlighting its varied functions in different cancer context (29).

Our study identified DDX17 as a novel regulator of AR stability in PCa, shedding new light on the intricate mechanisms that control AR signaling. We observed that DDX17 was overexpressed in enzalutamide-resistant PCa cell lines and clinical specimens, a correlation that aligns with poorer patient prognoses. These results underscore the function of DDX17 in enhancing AR stability by disrupting the SPOP-mediated ubiquitination pathway.

This discovery complements existing research on AR’s role in PCa and introduces a new layer by involving DDX17 in the regulatory framework. While previous research has thoroughly investigated AR and SPOP individually, our findings introduce a previously unknown interaction between DDX17 and SPOP, positioning DDX17 as a key regulator of AR stability. This adds depth to our understanding of how AR signaling persists despite therapeutic resistance.

Our results are consistent with those of other studies describing the role of DDX17 in other cancers, where it has been implicated in the promotion of oncogenesis. Taken together, these findings indicate that DDX17 might play a multifaceted role in cancer biology, aiding in tumor progression across different cancer types.

There are several limitations in this study. The primary experimental models were cell lines and clinical samples from a specific cohort, which might not fully capture the heterogeneity of PCa. Moreover, while our functional assays shed light on the role of DDX17, additional in vivo studies are necessary to confirm these results and assess their clinical significance. Future research should aim to evaluate the therapeutic potential of targeting DDX17 alongside existing AR-targeted therapies. Further investigation into how DDX17 modulation impacts AR signaling in vivo could provide deeper insights into its role in CRPC. Additionally, expanding the research to other cancer types in which DDX17 is involved may offer broader implications for its role in oncogenesis.

Conclusions

Our study identifies DDX17 as a novel regulator of AR protein stability in PCa. We demonstrate that DDX17 is upregulated in advanced and metastatic PCa and is associated with poor patient prognosis. Functionally, DDX17 promotes tumor cell proliferation and invasion by stabilizing AR protein levels through interference with SPOP-mediated ubiquitination and degradation. These findings reveal a previously unrecognized DDX17-SPOP-AR regulatory axis and suggest that targeting DDX17 may offer a new therapeutic strategy to combat AR-driven progression and treatment resistance in PCa. By revealing this novel regulatory pathway, our aim is to open up possibilities for developing targeted therapies that could circumvent resistance to current AR-targeted treatments and enhance outcomes for patients with CRPC. Further studies are warranted to validate these findings and explore their potential clinical applications.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the MDAR reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-167/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-167/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-167/prf

Funding: This work was supported by the National Natural Science Foundation of China (81872092, 82103276); Natural Science Foundation of Guangdong Province (2023A1515010321); Ganzhou Science and Technology Plan Project (2022--RC1341); Natural Science Foundation of Jiangxi Province (20224ACB206007); Jiangxi Province Ganpo Talent Support Program-Major Academic and Technical Leader Training Project (20232BCJ22018).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-167/coif). All authors report that this work was supported by the National Natural Science Foundation of China (81872092, 82103276); Natural Science Foundation of Guangdong Province (2023A1515010321); Ganzhou Science and Technology Plan Project (2022-- RC1341); Natural Science Foundation of Jiangxi Province (20224ACB206007); Jiangxi Province Ganpo Talent Support Program-Major Academic and Technical Leader Training Project (20232BCJ22018). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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