DUSP13 promotes prostate cancer progression by regulating the ERK1/2 pathway

Introduction

In 2022 Global Cancer Statistics, prostate cancer (PCa) had surpassed kidney cancer as the second most frequently identified male cancers behind lung cancers, and PCa had become the fifth deadly cancer (1). Compared with 2020, male mortality of PCa increased slightly (7.3% in 2022 vs. 6.8% in 2020) (1,2). In view of this trend, identifying novel therapeutic targets is crucial for improving the prognosis of patients.

Therapeutic regimens for localized PCa include active surveillance, surgery, chemotherapy, and radiotherapy (3). The initial systemic treatment regimen for metastatic PCa is “androgen deprivation therapy (ADT)” as well as “androgen receptor pathway inhibitors (ARPIs)”, often combined with docetaxel (4). Nevertheless, the therapeutic efficacy of ADT is often curtailed by the inevitable occurrence of drug resistance, propelling the majority of patients to “castration-resistant prostate cancer (CRPC)” or its metastatic form (mCRPC), at which stage the survival benefit provided by therapeutic regimen is limited for patients (5,6). In addition, current therapies are often accompanied by significant adverse reactions, which seriously affect the quality of life of patients (6,7). Therefore, it is urgent to develop more precise and effective targeted therapy.

Dual specificity phosphatases (DUSPs) are a family of enzymes that dephosphorylate both phosphotyrosine and phosphoserine/phosphothreonine residues on their substrates (8). DUSPs play diverse roles in regulating cell proliferation, differentiation, senescence, and apoptosis. Different DUSP family members exhibit either anti-tumor or pro-tumor effects depending on the cancer type. For instance, DUSP1 is significantly overexpressed in the serous ovarian cancer of high grade, leading to poorer clinical prognosis (9). DUSP13 high expression is significantly associated with microvascular invasion progression in liver cancer and is negatively correlated with overall survival (10). However, the function of DUSP13 in PCa remains unclear.

The MAPK-ERK pathway is often dysregulated in cancer and plays a crucial role in cell proliferation and survival (11). DUSPs are members of the MAPK phosphatases family and are divided into three subgroups on the basis of sequence homology, subcellular localization, and substrate specificity (12-15). DUSPs exhibit high selectivity for ERK and play a pivotal role in regulating ERK phosphorylation (16). Several DUSPs, including DUSP1 and DUSP6, have been shown to regulate ERK activity in a context-dependent manner (17,18). It is unclear whether DUSP13 affects PCa progression by regulating ERK1/2 pathway.

Herein, we explored the expression and function of DUSP13 in PCa. We demonstrated that DUSP13 is overexpressed in PCa cells and that its knockdown suppresses PCa progression. Mechanistically, DUSP13 exerts its carcinogenic effects by inhibiting ERK1/2 phosphorylation. Our results indicated that DUSP13 is a potential therapeutic target in PCa. We present this article in accordance with the MDAR and ARRIVE reporting checklists (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0341/rc).

Methods

Cell culture

RWPE-1, a normal human prostate epithelial cell was cultured in RWPE-1 specific medium (#iCell-h286-001b, iCell Bioscience Inc). PC-3, LNCaP and DU145, the human PCa cells, were cultured in RPMI1640 medium (#MA0215, MeilunBio) added 10% fetal bovine serum (FBS) (#FCS500, ExCell Bio) and 1% penicillin/streptomycin solution (#MA0110, MeilunBio) at 37 ℃ and 5% CO₂ in a saturated humidity incubator.

Cell transfection

PCa cells were transfected with lentiviruses (Zolgene Biotechnology). Three short hairpin RNAs (shRNAs) targeting distinct sites of DUSP13 (shRNA1, shRNA2, and shRNA3) and a non-targeting control were generated. shRNA2 showed the highest knockdown efficiency and is hereafter referred to as Sh-DUSP13; it was used for the main experiments. To exclude off-target effects, shRNA3 (hereafter Sh-DUSP13-3), which independently targets a different site of DUSP13, was used as a second independent shRNA. Transfection efficiency was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot at 48 hours after lentivirus infection.

Western blot

We used radioimmunoprecipitation assay (RIPA) lysis buffer to extract the total protein from cells and measured it by bicinchoninic acid (BCA). Protein electrophoresis experiments were conducted on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gels. Subsequently, the separated protein on the gel was transferred to a polyvinylidene fluoride (PVDF) membrane through a semi-dry PVDF transfer apparatus and the PVDF membrane was blocked with Tris-buffered saline with Tween-20 (TBST) blocking solution containing 5% skim milk, with the addition of primary antibody, The primary antibodies are listed below: GAPDH (Proteintech, 60004-1-lg, 1:50000, AB_2107436), DUSP13 (Proteintech, 10909-1-AP, 1:1000, AB_2230734), ERK1/2 (Proteintech, 11257-1-AP, 1:12000, AB_2139822) and p-ERK1/2 (Affinity, AF1015, 1:12000, AB_2834432). Washed with TBST Buffer. Incubated with second antibody (Goat anti-rabbit) conjugated to horseradish peroxidase (HRP) (SA00001-2, Proteintech) 1:2000 dilution for 1 hour at 25 ℃. The target strip was immersed in the developer for more than 30 s, and then placed in the imaging device for photography and development processing. Results were analyzed by ImageJ.

qRT-PCR

The total RNA of PCa cells and normal prostate epithelial cells are extracted by RNAiso Plus kit (#9109, TaKaRa). To synthesize first-strand cDNA, 1 μg total RNA was reverse-transcribed in 20 μL reaction by All-in-One First-Strand SuperMix (#MD80101, Magen Biotechnology). Triplicate qRT-PCR amplification of cDNA samples was performed by the 2× Universal SYBR Green qRT-PCR Supermix kits (#S2024L, US EVERBRIGHT), following the experiment protocols. The qRT-PCR reaction proceeded under the following thermal cycling protocol: 95 ℃ for 1 minute, 40 times of 95 ℃ for 35sec and 60 ℃ for 35sec. We used 2^−ΔΔCt method to calculate the relative RNA level. Used GAPDH as internal control for normalization. The primer sequences are listed in Table S1.

Cell counting kit-8 (CCK-8) assay

Transfected cells were seeded in 96-well plates. 10 μL CCK-8 solution (#MA0218, Meilune) was added at intervals of 24 hours for 3 times per well and incubated for 2 hours. Read the Absorbance at 450 nm with the spectrometer.

Scratch wounding healing assay

PCa cells were plated in 6-well plates at a density of 1×10⁶ cells/well. Scratch was made when cells fused, followed by washing with PBS and culturing in FBS-free medium. Images were respectively taken by an inverted microscope (Olympus, Japan) at 0 and 48 hours, and the scratch area was analyzed with ImageJ software. Computational formula: Migration rate (%) = (migration distance/original distance) ×100%. Experiments were conducted 3 times.

Transwell invasion assay

Prior to the experiment, a layer of extracellular matrix (ECM) gel was pre-coated on the upper layer of the transwell chamber. Once the gel was solidified, 200 μL cell suspension (containing 1×10⁵ cells) was added to the upper chamber. The culture medium supplemented with 20% FBS was added to the lower chamber, which acted as a chemoattractant. The culture plates were incubated for 48 hours at 37 ℃ in a 5% CO₂ atmosphere. After incubation, cells that had migrated onto the membrane were fixed using 4% paraformaldehyde and subsequently stained with 1% crystal violet. The cells passing through the membrane were observed by Olympus microscope, and the staining results were quantitatively analyzed by ImageJ software. All laboratories were repeated three times independently.

Apoptosis detection

PCa cells were seeded in 6-well plates at 1×10⁶ cells/well. After 48 hours lentiviral transduction with Sh-DUSP13 or NC, cells were collected, washed twice with cold PBS, and resuspended in 1× Annexin V binding buffer. Annexin V-APC and PI were added according to the manufacturer’s instructions (#AP107, MultiSciences). After incubation in the dark for 15 minutes at room temperature, apoptosis was immediately analyzed by flow cytometry without fixation. Each experiment was repeated three times independently.

Xenograft nude mice model

All animal experiments were performed under a project license (No. IACUC FJMU 2023-Y-0929) granted by Laboratory Animal Ethics Committee of Fujian Medical University, in compliance with institutional guidelines for the care and use of animals. All animal procedures were conducted at the Animal Center of Fujian Medical University. Lentiviral Sh-DUSP13 and negative control (NC) constructs (Zolgene Biotechnology) were used to generate stable PC-3 cell lines via infection and puromycin selection. Four-week-old male BALB/c nude mice (species: Mus musculus; genetic modification status: wild-type; weight: 12–15 g) were obtained from Fujian Anburui Biotech (#B201) and randomly allocated into two groups (NC and Sh-DUSP13, n=5 per group) using a random number generator. The random sequences were generated by independent researchers who did not participate in the experiment. The total number of mice used was 10. Each mouse received a subcutaneous injection of PC-3 cancer cells stably expressing either Sh-DUSP13 or NC. The subcutaneous xenograft model was chosen for its reproducibility and ease of monitoring tumor growth. Measure tumor volume every 3 days. The above experiments were carried out under double-blind conditions, and neither the operator nor the data evaluator was aware of the grouping assignments. To minimize potential confounding factors, all experimental procedures (including cell injection, tumor measurement, and sample collection) were randomized across different groups and performed at approximately the same time each day. Both animal handling and data collection followed standardized protocols. The mice were housed under specific pathogen-free (SPF) conditions at 22±2 ℃, with a 12-hour light/12-hour dark cycle, and had free access to food and water. No environmental enrichment was provided to avoid potential interference with tumor growth. Humane endpoints: tumor volume >1,500 mm³, ulceration, or weight loss >20%. Monitoring frequency: every 2 days. No unexpected adverse events occurred. After 21 days, the mice were humanely euthanized by gradual-fill CO₂ inhalation in accordance with AVMA guidelines.

Statistical analysis

Statistics analysis were conducted using GraphPad Prism 9.1. All data are represented as means ± standard deviation (SD). Normality was tested using the Shapiro-Wilk test, and homogeneity of variance was assessed by the Levene’s test. All data met the assumptions (P>0.05). Comparisons between two groups were made using Student’s t-test, because the data met the assumptions of normality and equal variance. For comparisons involving three or more groups, one-way analysis of variance (ANOVA) was applied. ANOVA was chosen because it allows simultaneous comparison of multiple groups while controlling Type I error rate. P<0.05 was statistically significant. *, P<0.05; **, P<0.01; ***, P<0.001. ns, no significance.

Results

DUSP13 is overexpressed in PCa cells

First, we used WB assay and qRT-PCR to detect DUSP13 expression. The levels of DUSP13 protein in the PC-3, DU145, and LNCaP cells were higher than in the RWPE-1 cells (Figure 1A) (P<0.05). Furthermore, the qRT-PCR results showed that DUSP13 mRNA was significantly upregulated in PCa cells (Figure 1B) (P<0.01). The above results demonstrated DUSP13 overexpression in PCa cells.

Figure 1 DUSP13 expression was upregulated in PCa cells. (A) Western blot showed the expression of DUSP13 protein in human normal prostate epithelial cells RWPE-1 and cancer cells PC-3, LNCaP and DU145. (B) qPCR showed the DUSP13 mRNA expression level in human normal prostate epithelial cells RWPE-1 and cancer cells PC-3, LNCaP and DU145. N=3; *, P<0.05; **, P<0.01; ***, P<0.001; ns, not significant. mRNA, messenger RNA; PCa, prostate cancer; qPCR, quantitative polymerase chain reaction.

Knockdown of DUSP13 suppressed PCa progression

Next, to explore the function of DUSP13 in PCa cells. We first verified the knockdown efficiency of the three shRNAs and selected shRNA2 (hereafter Sh-DUSP13), which showed the best knockdown efficiency, for subsequent experiments (Figure 2A,2B) (P<0.001). Functional assays showed that knockdown DUSP13 significantly inhibited proliferation (Figure 2C,2D) (P<0.001) and promoted apoptosis in PCa cells (Figure 2E,2F) (P<0.001). Then, the scratch assay and the transwell assay indicated that DUSP13 inhibition could significantly reduce PCa cells migration and invasion (Figure 3) (P<0.001). These results indicated that DUSP13 knockdown attenuated PCa progression and promoted PCa cells apoptosis.

Figure 2 Knockdown of DUSP13 suppressed the proliferation of PCa cells and promoted apoptosis. (A,B) Detection of the knockdown efficiency of DUSP13 in PCa cells PC-3 and DU145 by qPCR and Western blot. (C,D) CCK-8 assays showed the proliferation of PC-3 and DU145 cells between NC and Sh-DUSP13. (E,F) The apoptosis rate of PC-3 and DU145 cells between NC and Sh-DUSP13 was detected by flow cytometry assay. N=3; ***, P<0.001. APC, allophycocyanin; mRNA, messenger RNA; NC, negative control; OD, optical density; PCa, prostate cancer; PI, propidium iodide; qPCR, quantitative polymerase chain reaction; Sh, short hairpin.

Figure 3 Knockdown of DUSP13 suppressed the migration of PCa cells. (A,B) The scratch assay indicated knockdown of DUSP13 inhibited the migration of PC-3 and DU145 cells. (C,D) The Matrigel-coated transwell invasion assay showed that knockdown of DUSP13 inhibited the invasion of PC-3 and DU145 cells. N=3; **, P<0.01; ***, P<0.001. NC, negative control; PCa, prostate cancer; Sh, short hairpin.

Knockdown of DUSP13 inhibited tumor growth in vivo

Subsequently, we focused on the study of DUSP13 in the xenograft nude mice model. The tumor growth curve is shown in Figure 4A. We can observe that when DUSP13 was knocked down, the growth of PC-3 cells in the xenografted nude mouse was also reduced (Figure 4A,4B) (P<0.05). After injecting PC-3 cells into mice for 21 days, the mice were sacrificed. The research results indicated that DUSP13 knockdown in PCa decreased tumor growth in vivo.

Figure 4 Knockdown of DUSP13 suppressed tumor growth in xenograft nude mice model. (A) The tumor volume of PC-3 cells transfected with NC and Sh-DUSP13 lentiviral vector in xenograft nude mice models at different days. (B) The tumor weight of NC and Sh-DUSP13 groups after killing the xenograft nude mice. N=5; *, P<0.05; **, P<0.01. NC, negative control; Sh, short hairpin.

Knockdown of DUSP13 inhibited PCa progression through activating ERK1/2 pathway

Then, we explored the regulation mechanism of DUSP13 in PCa. We observed that knockdown of DUSP13 enhanced p-ERK1/2 protein expression. However, after treatment with the MEK inhibitor PD98059 (used to block ERK1/2 activation), p-ERK1/2 levels significantly decreased (Figure 5A) (P<0.001). We also found that MEK inhibitor treatment could partly inhibit the cell proliferation decrease and apoptosis increase caused by down-regulation of DUSP13 (Figure 5B,5C) (P<0.001). In addition, the scratch assay and the transwell assay indicated that MEK inhibition could partly inhibit cell migration decrease caused by the suppression of DUSP13 (Figure 5D,5E) (P<0.001).

Figure 5 Knockdown of DUSP13 suppressed PCa progression by activating the ERK1/2 pathway. (A) Western blot showed the expression of ERK1/2 and p-ERK1/2 in the NC, Sh-DUSP13, and Sh-DUSP13 + PD98059 groups. (B) CCK-8 assay showed the PC-3 cell proliferation of the NC, Sh-DUSP13, and Sh-DUSP13 + PD98059 groups. (C) Flow cytometry assay showed the apoptosis rate of PC-3 cells in the NC, Sh-DUSP13, and Sh-DUSP13 + PD98059 groups. (D,E) The scratch assay and transwell assay showed migration and invasion of PC-3 cells in the NC, Sh-DUSP13, and Sh-DUSP13 + PD98059 groups. N=3; ***, P<0.001. APC, allophycocyanin; NC, negative control; OD, optical density; PCa, prostate cancer; PI, propidium iodide; Sh, short hairpin.

A second independent shRNA confirms the ERK1/2-dependent anti-tumor effect of DUSP13 knockdown

To exclude potential off-target effects, we employed a second independent shRNA (Sh-DUSP13-3) targeting a distinct region of DUSP13. Sh-DUSP13-3 effectively reduced DUSP13 mRNA and protein levels (Figure 6A,6B) and, consistent with Sh-DUSP13, significantly inhibited proliferation (Figure 6C) and promoted apoptosis (Figure 6D) while suppressing invasion (Figure 6E) in PC-3 cells (P<0.05). Sh-DUSP13-3 also increased p-ERK1/2 levels (Figure 6A). Importantly, PD98059 alone (NC + PD98059) did not significantly alter proliferation, invasion, or apoptosis compared with NC, indicating that the observed phenotypes were not attributable to the inhibitor itself. In the Sh-DUSP13-3 + PD98059 group, PD98059 reduced p-ERK1/2 levels and partially reversed the changes in proliferation, apoptosis, and invasion induced by Sh-DUSP13-3 (Figure 6A-6E, P<0.05). Together, these results confirm that DUSP13 knockdown suppresses PCa progression through activation of the ERK1/2 pathway and rule out off-target effects.

Figure 6 A second independent shRNA (Sh-DUSP13-3) reproduces the effects of DUSP13 knockdown, and MEK inhibition partially rescues them in PC-3 cells. Four groups were compared: NC, NC + PD98059, Sh-DUSP13-3, and Sh-DUSP13-3 + PD98059. (A) Western blot and quantification of DUSP13, p-ERK1/2 and total ERK1/2, with GAPDH as loading control. (B) qRT-PCR of DUSP13 mRNA. (C) CCK-8 proliferation assay. (D) Flow cytometry apoptosis assay (Annexin V-APC/PI). (E) Matrigel-coated transwell invasion assay. N=3; ns, no significance; *, P<0.05; **, P<0.01; ***, P<0.001. APC, allophycocyanin; mRNA, messenger RNA; NC, negative control; OD, optical density; PI, propidium iodide; qRT-PCR, quantitative reverse transcription polymerase chain reaction; Sh, short hairpin.

Discussion

In the study, we demonstrated that DUSP13 is a previously unidentified regulator of PCa progression. We confirmed that DUSP13 was significantly overexpressed in PCa cell lines, and its knockdown could inhibit PCa progression, while promote apoptosis. Mechanistically, DUSP13 exerts carcinogenic effects by inhibiting ERK1/2 phosphorylation. These results establish the value of DUSP13 as a potential therapeutic target for PCa.

The role of MAPK-ERK pathway has been extensively studied in cancer (11,19). Although activation of ERK1/2 usually promotes cancer progression, recent research suggests that ERK signaling may represent a “double-edged sword” effect (20,21). When the excessive activation of ERK exceeds the optimal threshold, it can trigger a tumor suppressor response, such as oncogene-induced cell senescence or apoptosis (21-23). In an early study, activated forms of ERK1/2 were reported to be reduced or absent in late-stage prostate adenocarcinomas and metastatic deposits (24). Although other studies have reported elevated ERK activity in mCRPC (25), these seemingly conflicting observations are consistent with the context-dependent, “double-edged sword” nature of ERK signaling, in which either insufficient or excessive activation can constrain tumor cell survival. Consistent with the notion that excessive ERK activation can constrain tumor cell survival, we found that knockdown of DUSP13 increased p-ERK1/2 levels and inhibited tumor growth. Furthermore, inhibition of ERK alone did not significantly change proliferation and migration, and did not induce significant apoptosis, thus demonstrating that the phenotype of Sh-DUSP13 was caused by the ERK pathway rather than the inhibitor’s own effects. The observation that MEK inhibition can partially reverse the anti-tumor effect of DUSP13 knockdown further supports the conclusion that sustained ERK activation is involved in phenotype formation.

We propose a model in which DUSP13 acts as a regulator of ERK activity in PCa cells. In DUSP13-overexpressing PCa cells, ERK activity remained within the “tumorigenic window”—a level sufficient to support cell proliferation and survival, but below the threshold that triggers growth arrest. When DUSP13 was knocked down, this inhibition mechanism was lifted, resulting in continuous excessive activation of ERK, allowing cells to enter tumor inhibition mode.

The specific molecular mechanism of DUSP13 regulating ERK1/2 remains to be fully elucidated. As an atypical dual-specificity phosphatase, DUSP13 may directly dephosphorylate ERK1/2; however, DUSP13 is expressed as distinct isoforms and, like other atypical DUSPs, lacks a canonical kinase-interaction motif (26), suggesting that an indirect regulatory mechanism may also be involved. Another possibility is that DUSP13 acts on upstream regulators of the ERK pathway or other signal nodes that converge on ERK. In the future, it is necessary to further analyze the precise molecular association between DUSP13 and ERK1/2 through co-immunoprecipitation experiments, GST pull-down experiments and phosphorylated proteomics analysis.

The study has some limitations. First, the upstream regulatory factors and downstream effector molecules of DUSP13 in PCa are not yet clear. Secondly, the clinical significance of DUSP13 expression and its correlation with patient prognosis still need to be verified in a larger clinical cohort. Third, whether other signaling pathways (such as JNK, p38) are involved in the observed effect mechanism is not clear. Despite these limitations, this study confirmed that DUSP13 is a novel regulator of ERK signaling pathway in PCa. Fourth, DUSP13 overexpression was demonstrated in one normal prostate epithelial-derived cell line and three PCa cell lines; validation in additional cell lines and in clinical specimens is warranted. Fifth, we assessed steady-state p-ERK1/2 levels but did not examine the temporal dynamics of ERK phosphorylation; future studies using growth-factor stimulation time-course experiments are needed to clarify whether DUSP13 regulates the magnitude or the duration/sustainability of ERK activation.

From the perspective of translational medicine, targeting DUSP13 may provide a novel strategy for overcoming drug resistance in CRPC patients. Given that dysregulation of the RAF-MEK-ERK pathway is associated with PCa progression and androgen receptor inhibitor resistance (27), inhibition of DUSP13 may restore sensitivity to existing therapies. Future studies should explore the therapeutic effect of DUSP13 targeting strategy in CRPC preclinical model.

Conclusions

In conclusion, the study indicates that DUSP13 is overexpressed in PCa and promotes tumor progression by inhibiting ERK1/2 phosphorylation. Knockdown of DUSP13 can activate the ERK1/2 pathway, resulting in the PCa progression decrease and PCa cell apoptosis increase. These findings suggest that targeting DUSP13 is a promising strategy in the treatment of PCa.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the MDAR and ARRIVE reporting checklists. Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0341/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0341/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0341/prf

Funding: This study was supported by the Fujian Natural Science Foundation (No. 2023J01682).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0341/coif). The authors have no 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. All animal experiments were performed under a project license (No. IACUC FJMU 2023-Y-0929) granted by Laboratory Animal Ethics Committee of Fujian Medical University, in compliance with institutional guidelines for the care and use of animals.

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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