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. 2025 Aug 11;42(4):398–406. doi: 10.5114/ada.2025.153499

Sentrin/SUMO-specific protease 1 contributes to drug resistance in melanoma by mediating the deSUMOylation of Yes-associated protein

Bei Zhao 1, Yinghua Liu 2, Xuemei Tang 1, Shi Cheng 1,✉
PMCID: PMC12458072  PMID: 41001144

Abstract

Introduction

The effectiveness of chemotherapy in treating melanoma is limited due to drug resistance. Previous studies have shown that SENP1 (Sentrin/SUMO-specific protease 1) is related to the tumour hypoxic microenvironment, tumorigenesis and metastasis.

Aim

This study aimed to investigate its roles in drug resistance of melanoma.

Material and methods

Originally, a concentration of 2 μg/ml dacarbazine (DTIC) was employed in the treatment of A375 and M14 cell lines for a duration of 24 h. Subsequently, the cells were transferred to fresh medium and allowed to proliferate until reaching 80% of their maximum density. This treatment cycle was then repeated for a total of 10 days, following which the DTIC concentration was doubled. The establishment of drug-resistant cell lines for both A375 and M14 occurred after 8 months of sustained and continuous treatment. The expression level of SENP1 was monitored monthly using real-time reverse transcriptase-polymerase chain reaction (RT-qPCR), with a fold change above 1.5 compared to the untreated condition considered as significant.

Results

Finally, the study found that SENP1 was up-regulated by about 2.2-1.7 times in the drug-resistant cells. In addition, overexpression of SENP1 in normal A375 cells improved cell viability against DTIC. The study also found that Yes-associated protein (YAP) could form protein condensates in the cytoplasm while its expression was enhanced by SENP1-mediated deSUMOylation.

Conclusions

This study suggests that there is a positive correlation between the ubiquitin-specific protease SENP1 and drug resistance in melanoma. Its up-regulation may lead to changes in the deSUMOylation of YAP, activate the Hippo signalling pathway, and increase the resistance of melanoma to DTIC.

Keywords: melanoma, drug resistance, SENP1, YAP, Hippo signalling pathway

Introduction

Melanoma, a type of skin cancer arising from malignant lesions of melanocytes, has become the fastest growing cancer in men and the second fastest in women [1, 2]. In 2020, there were 324,635 new cases of skin melanoma worldwide, with 57,043 resulting in fatalities [3]. Early diagnosis can cure most melanomas; however, prognosis is poor once metastasis occurs, accounting for more than 80% of skin cancer deaths [4]. Median survival time for advanced melanoma patients is only 7.5 months, with a 2-year survival rate of approximately 15% and a 5-year survival rate of only 5% [5].

Surgery is the primary treatment method for early-stage skin melanoma, while adjuvant therapy such as chemotherapy or palliative therapy is crucial for middle-advanced melanoma patients [6]. Dacarbazine (DTIC), a conventional chemotherapy drug approved by the US Food and Drug Administration (US FDA), is commonly used to treat advanced melanoma [7]. However, chemotherapy is currently an unsatisfactory treatment due to drug resistance in melanoma, whether intrinsic or caused by the use of cytostatic drugs, which remains a significant problem. Generally, mutations in the B-Raf proto-oncogene (BRAF) gene are common in melanoma [8, 9]. Therefore, targeted therapies, such as BRAF inhibitors, may initially be effective, but resistance can emerge due to secondary mutations in the BRAF gene or other components of the mitogen-activated protein kinases (MAPK) signalling pathway [10, 11]. In addition, drug resistance can occur through the activation of alternative signalling pathways, such as receptor tyrosine kinase (RTK) or RAS pathways [12, 13]. This allows melanoma cells to bypass the inhibited pathways and continue to proliferate. Moreover, changes in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway can contribute to drug resistance by promoting cell survival and proliferation, independent of the inhibited pathway [14, 15]. Other studies also found that melanoma cells may up-regulate deoxyribonucleic acid (DNA) repair mechanisms, allowing them to overcome drug-induced DNA damage and survive treatment [16]. Nevertheless, the drug resistance mechanisms of melanoma have not been fully elucidated and need more studies.

SENP1 (Sentrin/SUMO-specific protease 1) is a protein involved in the post-translational modification process called SUMOylation, where Small Ubiquitin-like Modifier (SUMO) proteins are attached to target proteins. Notably, recent studies have identified the SENP1’s role in cancer drug resistance [17, 18]. For example, SENP1 has been implicated in the regulation of DNA repair processes. Enhanced DNA repair mechanisms in cancer cells can contribute to drug resistance by efficiently repairing drug-induced DNA damage [19], promoting genomic stability, and preventing cell death. In addition, SENP1 can affect various signalling pathways involved in cancer progression and drug response. It regulates the SUMOylation status of specific proteins, which may influence cellular responses to drugs and contribute to resistance [20]. Moreover, SENP1 may play a role in cellular responses to hypoxia, a condition often found in solid tumours. Hypoxia is associated with increased resistance to certain cancer therapies, and SENP1 could contribute to this resistance through its regulatory functions [21, 22]. However, the role of SENP1 in melanoma drug resistance has not been fully elucidated.

Besides, YAP is a transcriptional co-activator and a key downstream effector of the Hippo signalling pathway [23]. YAP plays a crucial role in regulating cell proliferation, survival, and organ size [24, 25]. While research on the role of YAP in melanoma is still ongoing, some studies suggest that YAP may contribute to melanoma development and progression. For example, YAP has been implicated in promoting cell proliferation and survival [26, 27]. In melanoma, increased YAP activity may contribute to uncontrolled cell growth, leading to tumour development and progression [28]. YAP has been linked to epithelial-mesenchymal transition (EMT), which enhances cancer cell invasion and metastasis [29]. In melanoma, increased YAP activity may contribute to the ability of melanoma cells to invade surrounding tissues and metastasize to distant organs [30–32]. Moreover, YAP has been linked to the inhibition of apoptosis, or programmed cell death [33, 34]. In melanoma, overactivation of YAP signalling may contribute to the resistance of melanoma cells to undergo apoptosis, allowing them to survive and proliferate [28, 35]. Whether YAP is involved in drug resistance in melanoma remains to be investigated.

To investigate the genes and signalling pathways especially the roles of SENP1 and YAP related to melanoma drug resistance, this study focused on A375 and M14 melanoma cells, obtaining drug-resistant cells by gradually increasing the concentration of DTIC. In this study, the roles of SENP1 and YAP as well as their interactions in drug resistance to DTIC was investigated. We tracked the expression of SENP1 and found its up-regulation in drug resistant cells. Further, the overexpression of SENP1 was also assessed to verify their association with drug resistance in melanoma. Finally, the study demonstrated that SENP1 enhances the Hippo signalling pathway by deSUMO-ylating YAP. This research will provide novel insights into the mechanisms of drug resistance in melanoma.

Material and methods

Cell lines, reagents and instruments

In this experiment, A375 and M14 cell lines used were preserved by the laboratory of Sichuan Provincial People’s Hospital, China. Originally, melanoma A375 cell line was purchased from American Type Culture Collection (ATCC, CRL-1619™, VA, USA) and melanoma M14 cell line was purchased from Yubo Biotechnology Co., Ltd. (YB-70287, Shanghai, China). The main reagents used in this study include: dacarbazine (DTIC, D129847, Aladdin, China), Annexin V-EGFP/PI Cell Apoptosis Detection Kit (TransGen, Beijing, China), dimethyl sulfoxide (DMSO, Solarbio, Beijing, China), skimmed milk powder (Solarbio, Beijing, China), Tris-buffered saline with Tween-20 (TBST) buffer (Solarbio, Beijing, China), phosphate buffer (Solarbio, Beijing, China), tetramethylethylenediamine (TEMED, Aladdin, Shanghai, China), ammonium persulfate (Aladdin, Shanghai, China), Coomassie Brilliant Blue (Aladdin, Shanghai, China), SYBR qPCR Master Mix (Vazyme, Nanjing, China). The main instruments used in this study included Multifunctional microplate detector (Synergy HTX, Biotek, USA), gel imaging system (ChemiDoc™ XRS+, Bio-Rad, USA), flow cytometer (FACSCalibur, BD Biosciences, USA) and real-time quantitative PCR (QuantStudio™ 3 Real-Time PCR System, ABI, USA).

Establishment of drug resistant cells

A375 and M14 cells were cultured using the Dulbecco’s modified Eagle’s medium (DMEM) complete medium containing 10% foetal bovine serum (FBS). DTIC was dissolved in normal saline. A375 and M14 cells suspension (1 × 105 cells/ml) at the logarithmic growth stage was shocked with DTIC at the initial induction dose (2 μg/ml). After culture for 24 h, the drug-containing medium was discarded, and inoculated into a new culture vial at the concentration of 1 × 105 cells/ml. The next day, the solution was changed, and the suspension was shocked again when the vial gradually grew to 80% of their maximum density. Each dose was maintained for 10 d, then the drug induction dose was doubled. By the end of the 8th month, a cell line with resistance to 2 mg/ml DTIC could be induced.

Real-time quantitative PCR (RT-qPCR) analysis

Real-time quantitative PCR was used to verify the mRNA level of the target gene in the control group and the experimental group, and to detect whether it was in line with the change in transcription level. 1 μl of each dilution was used as template for following qRT-PCR reaction. The qPCR reaction was carried out in 10 μl reactions containing 5 μl of qPCR Master Mix (Vazyme, Nanjing, China), 3 μl dH2O, 1 μl diluted template cDNA and 1 μl of each PCR primer, employing the QuantStudio™ 3 Real-Time PCR System (Applied Biosystems, CA, USA) [36]. Three technical replicates were performed for each condition. Data analysis was carried out using the QuantStudio 3 software (Applied Biosystems, CA, USA) and the 2-ΔΔCT method [37].

Construction of gene-overexpressed cell lines

The third-generation lentivirus packaging system was utilized to transfect pCMV-R + pMDG + target gene to HEK293T cells. After expression identification, they were concentrated with 10% PEG8000, followed by the addition of venom and Polybrene (8 μg/ml) at a volume ratio of 1 : 100 to infect melanoma cells. The culture medium was replaced after 12 h of infection with A375 melanoma cells. The medium was replaced with fresh medium containing puromycin (200 ng/ml), and screen/screened for 14 days to establish a stable expression cell line. The protein expression level of SENP1 was detected by western blot.

Apoptosis detection

Cell apoptosis was detected by flow cytometry. The cells in the control group and the experimental group were inoculated in 24-well plates (5 × 104 cells/well). After 48 h of culture, the cells were collected (centrifuged at 1000 rpm for 5 min), washed once with phosphate buffer, and then added with 100 μl Annevix Binding Buffer. After that, 5 μl Annevix Fluorescein isothiocyanate (FITC) and 5 μl propidium iodide (PI) were added successively and kept in dark at room temperature for 15 min. Finally, apoptosis detection was performed on flow cytometry after adding 150 μl Annevix Binding Buffer.

Western Blot (WB)b

General protocol for WB: cells with different treatment factors were collected, lysed with RIPA strong lysate, and total protein was extracted and quantified with a NanoDrop® ND-1000 UV-Vis Spectrophotometer. 50 μg of total protein taken from each sample was electrophoresed and transferred to a membrane [polyvinylidene fluoride ethylene (polyvinylidene fluoride, PVDF) membrane], following/followed by block with 5% skimmed milk powder/washing buffer (TBST buffer) on a shaker at room temperature for 1 h. The primary antibody was bound overnight at 4°C then washed 3 times with TBST, followed by secondary antibody binding and incubated at room temperature on a shaker for 1 h. After that, the sample was washed 3 times with TBST and added with ECL chemiluminescence reagent for 1.5–2 min. Finally, the result was observed with a gel imaging system.

For co-immunoprecipitation (co-IP) assay, YAP with 3x Flag tag was overexpressed via the lentiviral vector pITA and introduced into A375 cell lines. Cell extracts were prepared from non-protein denatured lysates, following/followed by addition with anti-Flag agarose magnetic beads. After 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gel electrophoresis, transmembrane and sealing, primary antibody of YAP was utilized for incubation. Further, second antibody Horseradish peroxidase (HRP) was coupled and electrochemiluminescence (ECL) colour was detected by MiniChemi™ Chemiluminescence imager (SageCreation, Beijing, China).

For interaction exploration between SENP1 and YAP, expression of YAP was detected in A375 with control vector and A375-SEOE. MG132 was utilized as the protease inhibitor while cycloheximide (CHX) served as the protein synthesis inhibitor. Hinokiflavone (HF) was used as the inhibitor of SENP1. β-Actin was taken as the reference.

Fluorescence recovery after photobleaching

A fused protein of GFP-YAP (GFP was green fluorescent protein) was realized with the vector pITA and introduced into A375 cell lines. GFP-YAP-IDR was achieved via constructing their expression with the pEGX-6P-1 vector and introduced into Escherichia coli BL 21. The protein expression was induced with isopropyl-beta-d-thiogalactopyranoside (IPTG), followed by protein purification. The fluorescence recovery after photobleaching assay was performed with the laser scanning confocal microscope. Meanwhile, whether high-salt solution and organic solvent can eliminate foci formation was evaluated.

Statistical analysis

Statistical software SPSS 18.0 was used for data analysis. Measurement data were expressed as `x ± s. Comparisons among multiple groups were performed by one-way analysis of variance. Significant differences between two groups were performed/determined by t-test, and p < 0.05 was considered statistically significant.

Results

Validation of genes potentially related with drug resistance

To generate drug-resistant melanoma cell lines, we treated A375 and M14 cells in the logarithmic phase with an increasing concentration of DTIC (details were given in the Methods section). Following continuous DTIC treatment of A375 and M14 melanoma cell lines for 8 months, we assessed the tolerance of both experimental and control groups. The parent cell lines were used as the control group (i.e., A375-WT and M14-WT), while the resulting drug-resistant cell line was the experimental group (DTIC-resistant, A375-DR and M14-DR). SENP1 is a key protease that is essential in the process of SUMOylation and deSUMOylation, regulating the cell cycle, proliferation, and apoptosis. SENP1 is also the most deeply studied SUMO protein closely related to tumours [38]. The expression level of SENP1 was monitored monthly using RT-qPCR (data not shown), with a fold change above 1.5 compared to the untreated condition considered as significant. Finally, we used RT-qPCR to confirm the expression of SENP1 in the obtained cell lines after 8 months. As illustrated in Figure 1, the expression levels of SENP1 in the resistant strains, A375-DR and M14-DR, respectively, were significantly up-regulated. Specifically, compared to the control group A375-WT, A375-DR showed a 2.2 ±0.12-fold increase in the relative expression of SENP1 (p < 0.001). Moreover, relative to the control group M14-WT, the relative expression of SENP1 in M14-DR increased by 1.7 ±0.14 times (p < 0.001). These results indicate that the expression levels of SENP1 and YAP in drug-resistant cell lines are indeed increased and may contribute to the drug resistance of melanoma.

Figure 1.

Figure 1

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RT-qPCR analysis of the expression levels of SENP1 in different cell lines. The relative expression of SENP1 in the drugresistant melanoma cell lines A375-DR and M14-DR and the control groups A375-WT and M14-WT. (**p < 0.01, ***p < 0.001)

Overexpression of SENP1 in normal A375 cell improved cell viability against DTIC

SENP1 is the sentrin-specific protease 1 related with catalysing maturation SUMO protein (small ubiquitin-related modifier) [39]. To investigate the association between the key gene SENP1 and drug resistance, we attempted to overexpress it in normal A375 cell lines (A375-SEOE). A375 cells containing a control plasmid were used as the blank group (A375-CT). Firstly, qPCR was employed to assess the expression level of SENP1 in A375-CT and A375-SEOE. As demonstrated in Figure 2 A, SENP1 was significantly up-regulated in A375-SEOE compared to that in A375-CT, indicating the successful overexpression. Subsequently, the viability of A375-CT and A375-SEOE towards DTIC at different concentrations was measured. As expected, although the viability decreased with the increasing DTIC concentration in both A375-CT and A375-SEOE, it was significantly higher in A375-SEOE than in A375-CT, especially when the DTIC concentration was below 2 μM (Figure 2 B). Our findings suggest that SENP1 indeed contributes to drug tolerance.

Figure 2.

Figure 2

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Characterization of overexpression of SENP1 in normal A375 cells/cell lines. A – RT-qPCR detection of the expression levels in A375-CT an A375-SEOE. B – Viability of A375-CT and A375-SEOE against DTIC with different concentrations

YAP is a protein capable of forming an intracellular condensate

YAP is a transcriptional coactivator that lacks a DNA-binding motif but possesses a potent transactivation domain at its C-terminus. YAP’s N-terminus contains an association domain that interacts with the TEA domain (TEAD) family of DNA-binding proteins, which are involved in YAP’s growth-promoting activity [40]. To explore the potential for YAP to form macromolecular condensates, bioinformatic predictions were first conducted using the Predictor of Natural Disordered Regions (PONDR, http://www.pondr.com/). The analysis revealed that YAP’s inner disordered region (IDR) can form intracellular condensates (Figure 3 A). Subsequently, fluorescence recovery after photobleaching was used to evaluate the feasibility of YAP condensate formation by constructing a fusion protein of GFP-YFP in A375 cell lines. Interestingly, clear intracellular condensates could be detected with a normalized recovery time of approximately 90 s (Figures 3 B, C). Furthermore, the condensate could be disrupted by 4% hexanediol (Figure 3 D), and the GFP-YAP-IDR (a truncated sequence of YAP containing only its IDR region) could form protein condensates in vitro under 2.5 μM (Figure 3 E).

Figure 3.

Figure 3

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Characterization of intracellular condensate capability of YAP. A – Bioinformatic prediction of YAP via the Predictor of Natural Disordered Regions. B – Fluorescence recovery after photobleaching assay in A375 cells with GFP-fused YAP protein. C – The normalized recovery time course of GFP-fused YAP. D – The influence of hexanediol on the intracellular condensate capability of YAP. E – The in vitro assay to investigate the condensate capability using GFP-fused YAP-IDR (only the internal disordered regions)

SENP1 enhances Hippo signalling pathway by deSUMOylation of YAP

Since SENP1 and YAP were both up-regulated in DTIC-resistant cells, we aimed to investigate their potential interactions in the following study. A co-immunoprecipitation (co-IP) assay was performed to determine whether interactions occurred between SENP1 and YAP. As depicted in Figure 4 A, SENP1 was clearly detected in the Flag-tagged purified protein of YAP, indicating that they indeed interacted. Given that SENP1 is involved in deSUMOylation, we explored the impact of SENP1 on YAP. Firstly, we used MG132 as a protease inhibitor and cycloheximide (CHX) as a protein synthesis inhibitor to investigate the effect of SENP1 overexpression in A375-SEOE on YAP stability compared to that in A375-CT (control). Our results showed that the overexpression of SENP1 in A375-SEOE enhanced YAP stability compared to that in A375-CT (Figure 4 B). Next, we evaluated the SUMOylation status of YAP in the presence of SENP1. We used hinokiflavone, an inhibitor of SENP1, to investigate the effect of SENP1 on YAP. As expected, the stability of YAP was significantly decreased after treatment with hinokiflavone compared to that in the control group (Figure 5 A). Meanwhile, the SUMOylation degree of YAP was maintained when co-incubated with HA-Ub, SENP1, and hinokiflavone (Figure 5 B). In conclusion, our findings demonstrate that SENP1 can enhance the Hippo signalling pathway by deSUMOylating YAP, thereby altering the drug resistance to DTIC.

Figure 4.

Figure 4

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The interaction between SENP1 and YAP. A – Co-IP assay via the flag-tagged YAP. B – Effect of overexpression of SENP1 on the stability of YAP

Figure 5.

Figure 5

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The regulation of SENP1 on YAP. A – Effect of SENP1 on the stability of YAP with the addition of hinokiflavone. B – Effect of SENP1 on the SUMOylation of YAP with the addition of hinokiflavone

Discussion

Melanoma arises from genetic mutations in melanocytes and can be found in the skin, eyes, inner ear and pia mater [41]. In addition, melanoma accounts for approximately 1% of all skin malignancies and is the most aggressive and deadly form of skin cancer [42]. For patients with stage I-IIIB melanoma, surgery is the main treatment method along with chemotherapy, radiotherapy, immunotherapy, targeted therapy, etc. [43]. Besides the adverse reactions of skin and digestive tract toxicity due to the lack of specificity of drugs [44], the drug resistance of lesions to chemotherapy is also the current dilemma in the treatment of melanoma [45]. Therefore, studying the causes of drug resistance in melanoma is of great significance for improving the efficacy of chemotherapy.

Protein ubiquitination modification is an important mechanism for maintaining the homeostasis of substrate proteins. It plays a key role in regulating protein-protein interactions, subcellular localization, gene transcription activity, and target protein stability [46, 47]. In addition, studies have shown that SENP1 is associated with tumour drug resistance. For example, Gao et al. found that SENP1 was aberrantly overexpressed in lung cancer cells, whose overexpression had a protective effect on alastine or cisplatin-treated lung cancer cells [48]. In addition, Chen et al. found that SENP1 protein accumulated in large quantities in the constructed human colon cancer cell lines resistant to irinotecan, knockdown of whom reduced the migration ability of cancer cells [49]. In this study, it was found that the expression level of SENP1 was significantly increased in DTIC-resistant melanoma cells. Combined with previous reports, it is likely to play an important role in the drug resistance of melanoma.

The Hippo signalling pathway first discovered in Drosophila is highly conserved in mammals [50]. Loss or overactivation of the Hippo pathway may lead to abnormal cell growth and tumorigenesis. In previous studies, researchers found that genes related to the Hippo pathway are often abnormally expressed in various cancers such as liver cancer, colorectal cancer, and lung cancer, and are related to the occurrence and development of tumours [51, 52]. The core components of the mammalian Hippo signalling pathway include cytoplasmic kinase module and a nuclear transcriptional module. Among them, YAP belonging to the nuclear transcriptional module has the function of promoting cancer [27]. Though the roles of SNEP1 and YAP have been separately elucidated, whether interactions existed between them remained unclear. Previously, Li et al. found that SENP1 mediated the deSUMOylation of JAK2 and regulated its kinase activity then leading to platinum drug resistance [20]. In addition, Zhang et al. demonstrated that potent SENP1 inhibitors that inactivated SENP1/JAK2/STAT signalling pathway could overcome platinum drug resistance in ovarian cancer [38]. The emerging roles of SUMOylation in the tumour microenvironment and therapeutic implications have been concerned, suggesting it could alter the drug resistance via SUMOylation of the target gene [53]. Consistently in this study, combined with the abnormal expression of SENP1, we further demonstrated that the SENP1 gene is involved in the regulation of the Hippo signalling pathway, especially the regulation of YAP.

Conclusions

Exploring the mechanisms of drug resistance in melanoma is of great importance for modifying the efficacy of chemotherapy in the future. In this study, we identified that SENP1 and YAP were related with drug resistance to DTIC. SENP1 was upregulated by about 2.2–1.7 times in the two drug resistant cell lines, respectively. In addition, overexpression of SENP1 in normal A375 cell improved cell viability against DTIC, whose viability was significantly enhanced especially when the DTIC concentration was below 2 μM. Moreover, the interaction between SENP1 and YAP was explored and their relationship with drug resistance was predicted. The study found that SENP1 contributed to drug resistance in melanoma by mediating the deSUMOylation of YAP. In the following work, the deep mechanisms of SENP1 and YAP participating in the drug resistance are worthy of elucidation.

Funding Statement

Funding The study was supported by grants from Sichuan Science and Technology Program (No. 2023NSFSC1549) and Health Science Research Project of Sichuan Province (No. 2023-218).

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

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