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SPICE1 promotes osteosarcoma growth by enhancing the deubiquitination of FASN mediated by USP10

Journal of Translational Medicine volume 23, Article number: 220 (2025) Cite this article

Abstract

Background

Osteosarcoma (OS) is recognized as a prevalent primary bone malignancy, particularly affecting adolescents during their growth spurts. Despite its clinical significance, the underlying biological characteristics and associated prognostic factors remain incompletely understood. The identification of novel molecular players involved in osteosarcoma progression could enhance our understanding of its pathogenesis and potentially inform patient management strategies.

Methods

In this study, we investigated the expression levels of Spindle and Centriole-Associated Protein 1 (SPICE1) in OS cells and tissues through quantitative analyses. We performed in vitro and in vivo experiments to evaluate the proliferation effects of SPICE1 on OS cells. Additionally, we explored the mechanistic interactions between SPICE1, Fatty Acid Synthase (FASN), and ubiquitin-specific peptidase 10 (USP10) through co-immunoprecipitation and mutation analyses, including the design of a peptide to inhibit the SPICE1-FASN interaction.

Results

Our findings revealed that SPICE1 is significantly overexpressed in OS samples. Furthermore, this high expression correlates with poor patient prognosis. The elevated levels of SPICE1 were found to promote OS cell proliferation by inhibiting the ubiquitination of FASN, consequently enhancing FASN protein stability. Additionally, SPICE1 was shown to facilitate the interaction between USP10 and FASN, promoting FASN deubiquitination, with specific amino acid interactions identified between USP10 and FASN that are necessary for this process.

Conclusion

This study elucidates the role of SPICE1 as a potential oncogene in OS, highlighting its contribution to tumor growth through the modulation of FASN stability. Importantly, our results suggest that targeting the SPICE1/USP10/FASN signaling axis could offer a novel therapeutic approach for treating OS. Future investigations should focus on the development of specific inhibitors that disrupt this pathway, ultimately leading to improved clinical outcomes for patients with OS.

Introduction

Osteosarcoma (OS) represents the most frequently occurring primary malignant bone tumor, predominantly impacting children and adolescents, with an estimated global incidence of approximately 3.4 cases per million annually [1,2,3,4]. Despite advancements in therapeutic approaches for OS, there has been a negligible enhancement in patient prognoses over recent decades [5]. Consequently, it is imperative to pursue research that deepens our comprehension of the molecular mechanisms underlying OS carcinogenesis and aids in the identification of prospective therapeutic targets.

Spindle and Centriole-Associated Protein 1 (SPICE1) is a protein associated with mitosis, playing a pivotal role in centriole duplication, bipolar spindle formation, and chromosome congression [6]. SPICE1 interacts with CEP120, facilitating procentriole elongation and the recruitment of capping proteins essential for procentriole formation [7]. Additionally, SPICE1 serves as a substrate for phosphorylation by aurora kinase, and its dysregulation can result in mitotic abnormalities [8]. It is well-documented that such mitotic anomalies can lead to chromosomal instability, thereby fostering genetic instability and tumorigenesis [9, 10]. For instance, chromosomal instability can perpetually activate the cGAS–STING pathway, creating a pro-metastatic tumor microenvironment [11]. Although SPICE1's critical role in cell mitosis is well-established, its specific function and mechanism in tumors remain unexplored.

To the best of our knowledge, this study is the first to identify SPICE1 as a potential novel oncogene. Our findings demonstrate that the overexpression of SPICE1 significantly enhances cell proliferation and tumor growth. Furthermore, we reveal that SPICE1 inhibits the ubiquitination and degradation of Fatty Acid Synthase (FASN) by augmenting its interaction with the deubiquitinating enzyme USP10. Notably, we employed a peptide derived from SPICE1 amino acids 325–437 to disrupt the SPICE1–FASN interaction, which effectively compromised SPICE1’s functionality. This research suggests that targeting the SPICE1/USP10/FASN signaling pathway may provide a novel therapeutic strategy for the treatment of OS.

Materials and methods

Cell lines

The cell lines utilized in this study, namely 143B, HOS, U2-OS, MG-63, hFOB 1.19, and HEK293T, were obtained from the American Type Culture Collection (ATCC) between 2017 and 2020, as well as from the National Collection of Authenticated Cell Cultures in 2021. All cell lines underwent authentication through short tandem repeat (STR) analysis, were confirmed to be free of mycoplasma contamination, and were maintained under standard conditions (5% CO2 and 37 °C) in a humidified incubator.

Reagents, antibodies, and constructs

The reagents employed in this research included MG132 (HY-13259), cycloheximide (HY-12320), a protease inhibitor cocktail (HY-K0010), and protein A/G magnetic beads (HY-K0202), all sourced from MedChemExpress (China). Cell culture materials were procured from Invitrogen (Carlsbad, CA, USA). Antibodies were obtained from various suppliers: Proteintech (GAPDH, 60004-1-Ig; Bax, 50599-2-Ig), Abcam (SPICE1, ab117801; USP10, ab109219), Cell Signaling Technology (Normal Rabbit IgG, 2729S; FASN, 3180S; Bcl-xl, 2764S), Sigma (Flag M2 Magnetic Beads, M8823; Flag, F3165; HA, H6908; Myc, 06–549), and Beyotime (Alexa-Fluor-488 and Alexa-Fluor-555 conjugated anti-rabbit/mouse secondary antibodies, A0423/A0428; A0453/A0460). Plasmids encoding SPICE1, FASN, and USP10 were acquired from MiaoLingBio (China). Truncated plasmids were generated using a mutation kit from Vazyme (C112; China) with the full-length plasmid serving as the template.

Western blotting

For protein analysis, cells or tissue samples were washed with cold phosphate-buffered saline (PBS), resuspended in RIPA buffer (Thermo Fisher Scientific) supplemented with phosphatase/protease inhibitors, and centrifuged. The resulting supernatants were subjected to SDS-PAGE, followed by transfer to PVDF membranes (Millipore). Membranes were blocked with 5% skim milk in TBST at 4 °C for one hour, incubated overnight with primary antibodies, washed three times with TBST, and subsequently incubated with HRP-conjugated secondary antibodies. Protein bands were visualized using a Bio-Rad ChemiDoc MP system.

Immunoprecipitation

To investigate the interactions among SPICE1, USP10, and FASN, HEK293T cells were co-transfected with Flag-SPICE1, HA-FASN, and Myc-USP10. Following transfection, cells were washed, resuspended in Pierce IP buffer (Thermo Fisher Scientific), and centrifuged. The supernatants were incubated with Flag M2 (Sigma) or HA (MCE) magnetic beads at 4 °C. Beads were subsequently washed with cold PBST, mixed with SDS sample buffer, and analyzed via western blotting. For endogenous interactions, 143B and HOS cells were lysed in Pierce IP buffer, centrifuged, and the supernatants were collected. These were incubated with primary antibodies or homologous IgG overnight at 4 °C, followed by incubation with protein G/A-conjugated beads (ThermoFisher). Beads were washed, mixed with SDS sample buffer, and subjected to western blotting analysis.

RNA extraction and quantitative RT-PCR

RNA was extracted from cells using the EZ-press RNA purification kit Plus, following the provided protocol (B0004-plus; EZBioscience, Roseville, MN, USA). Cells were washed with cold PBS, lysed, and DNA was removed using spin columns. The RNA was eluted, and its concentration was quantified. Total RNA (1 µg) was reverse-transcribed into cDNA using HiScript III All-in-one RT SuperMix Perfect for qPCR (R333-01). Quantitative RT-PCR was performed using Vazyme’s SYBR Green kit (Q131-02/03) on a Bio-Rad CFX Connect system, with GAPDH serving as the control. Primers were designed using Oligo7 and validated with BLAST, yielding PCR products ranging from 100 to 200 base pairs. Primer sequences are provided in the Supplementary Table.

Cell proliferation assay

Cell proliferation was assessed using 143B or HOS cells (3 × 103 cells/well) cultured in six-well plates for 7 to 10 days, followed by staining with crystal violet. Colonies containing more than 50 cells were counted. Additionally, a CCK8 assay was conducted with 1 × 103 cells seeded in 96-well plates, incubated with a 1:10 diluted CCK8 reagent, and cell viability was measured at OD450 after two hours. EdU-labeled staining was also employed for proliferation detection, with cells seeded in 96-well plates, cultured overnight, and incubated with diluted EdU solution for an additional hour.

Lentivirus infection and xenografts

The lenti-X-shRNA construct (pGV493-GFP) for shRNA-SPICE1 knockdown was prepared using GeneChem, with target sequences listed in the Supplementary Table S2. Following infection, cells were treated with puromycin to select for stable integrants. The LentiX construct (pGL180-GFP) for SPICE1 overexpression was prepared using Obio. For in vivo experiments, 3 × 106 stably infected 143B cells were resuspended in serum-free α-MEM and injected into 5-week-old female BALB/c-nu mice. Tumor size was measured every other day post-injection, and volume was calculated using the formula V = (L × W2)/2. After four weeks, xenografts were harvested for analysis.

Immunofluorescence

To observe the colocalization of SPICE1, USP10, and FASN, 143B or HOS cells were transfected with Flag-SPICE1 or Myc-USP10, seeded in confocal dishes, fixed in 4% paraformaldehyde (PFA), and permeabilized with 0.1% Triton X-100. Cells were incubated overnight at 4 °C with primary antibodies in PBS containing 2% BSA, washed, and incubated with Alexa Fluor 488/555-conjugated secondary antibodies. Images were captured using a Stellaris 5 confocal microscope (Leica).

Statistical analysis

All experiments were performed in triplicate. Data are presented as mean ± standard deviation (SD). Differences between two groups were analyzed using Student’s t-test or one-way ANOVA, with significance set at P < 0.05. All statistical analyses were conducted using SPSS software (version 13.0; SPSS Inc.).

Results

SPICE1 is highly expressed in OS and correlates with poor patient prognosis

To identify novel biomarkers associated with osteosarcoma (OS), we performed ribonucleic acid sequencing (RNA-seq) analysis on three paired samples of OS and adjacent normal tissues. This analysis revealed a total of 1622 differentially expressed genes, comprising 401 genes that were up-regulated and 1221 genes that were down-regulated (Fig. 1A). We subsequently retrieved OS data from the TARGET database and conducted univariate Cox regression analysis, identifying 342 genes associated with poor prognosis in OS (Fig. 1B). A Venn diagram analysis indicated the presence of five common genes (SPICE1, ZDHHC23, MYO6, TRPS1, and KLF5) shared between the 342 high-risk genes and the 401 up-regulated genes (Fig. 1B), which were further visualized using a heat map (Fig. 1C). Among these, SPICE1 exhibited the highest hazard ratio (HR) of 2.467 (Fig. 1D). Kaplan–Meier survival analysis demonstrated that patients with elevated SPICE1 expression experienced significantly shorter overall and progression-free survival times (Fig. 1E, F). Furthermore, we assessed SPICE1 expression in OS tissues and cell lines, revealing through western blotting and qRT-PCR analyses that SPICE1 was markedly overexpressed in both OS samples and cell lines (Fig. 1G, H; Supplementary Fig. 1A, B). These findings suggest that SPICE1 may serve as a promising therapeutic target for OS.

Fig. 1
figure 1

SPICE1 is highly expressed in OS. The RNA-seq analysis using a volcanic map revealed 1622 genes that were expressed differently in OS and its adjacent tissues, with 401 genes showing increased expression and 1221 genes showing decreased expression (A). The Venn diagram analysis compared 401 up-regulated genes and 342 high-risk genes linked to poor overall survival in the TARGET database. This analysis identified five common genes: SPICE1, ZDHHC23, MYO6, TRPS1, and KLF5 (B). Subsequently, these genes were visualized using a heat map (C). The forest map displayed the HR values for five genes, with SPICE1 achieving the highest score (D). Next, we analyzed the survival data of OS patients from the TARGET database, focusing on the relationship with SPICE1 expression. Our analysis revealed that high levels of SPICE1 expression are associated with shorter overall survival (E) and progression-free survival (F) in patients with OS. SPICE1 expression was significantly higher in OS tissues compared to the paired normal tissues, as demonstrated by western blotting (G) and qRT-PCR (H) assays. *P < 0.05; **P < 0.01; ***P < 0.001; by two-tailed Student’s t-test

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SPICE1 promotes OS cell proliferation and tumor growth

Utilizing a lentiviral system, we stably expressed or silenced SPICE1 in HOS and 143B cells. The efficacy of SPICE1 overexpression and knockdown was confirmed through western blotting analysis and qRT-PCR (Supplementary Fig. 1 C-H). The silencing of SPICE1 resulted in a significant reduction in cell proliferation in both HOS and 143B cells. Conversely, the overexpression of SPICE1 led to enhanced proliferation of OS cells, as evidenced by CCK8, colony formation, and EdU assays (Fig. 2A–L). Additionally, SPICE1 knockdown markedly inhibited tumor growth in nude mice (Fig. 2M; Supplementary Fig. 1I), while SPICE1 overexpression accelerated tumor growth (Fig. 2N; Supplementary Fig. 1J). Collectively, these results indicate that SPICE1 functions as a proto-oncogene in OS.

Fig. 2
figure 2

SPICE1 promotes OS cell proliferation and tumor growth. 143B and HOS cells with both stably express and silence SPICE1 were subjected to CCK8 assays (A–D), colony formation assays (E–H), or EdU assays (I–L). The images and weights of the subcutaneous xenograft tumors for each group at 28 days post-injection were recorded (M, N). The data was presented as means ± SD. *P < 0.05; **P < 0.01; ***P < 0.001; by two-tailed Student’s t-test

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SPICE1 interacts with FASN and inhibits its ubiquitination

To elucidate the molecular mechanisms underlying the oncogenic role of SPICE1, we identified potential binding partners of SPICE1 through mass spectrometry. The results indicated that FASN exhibited the highest binding score (Supplementary Excel 1), suggesting a strong interaction with SPICE1. FASN is known for its high expression in various tumors and its role in promoting tumor progression [12]. Our previous studies have established that FASN is crucial for the growth and metastasis of OS [13,14,15]. To validate our hypothesis regarding the role of FASN in SPICE1 function in OS, we confirmed the presence of FASN in the immunoprecipitation of SPICE1 via silver staining (Fig. 3A). Co-transfection of HEK293T cells with Flag-SPICE1 and HA-FASN followed by co-immunoprecipitation and western blotting demonstrated that SPICE1 could pull down FASN, and vice versa (Fig. 3B). Similar results were obtained in OS cells through co-immunoprecipitation of endogenous proteins (Fig. 3C). Furthermore, immunofluorescence assays confirmed the co-localization of SPICE1 with FASN in OS cells (Fig. 3D). The SPICE1 protein contains two significant coiled-coil domains, CC1 and CC2. Co-immunoprecipitation assays revealed that the CC1 domain of SPICE1 is essential for its interaction with FASN (Fig. 3E). Notably, SPICE1 knockdown resulted in decreased FASN protein levels without affecting its mRNA expression, while SPICE1 overexpression led to increased FASN protein levels (Fig. 3F; Supplementary Fig. 2A, B). To further investigate the stability of FASN protein, we treated OS cells with cycloheximide (CHX), finding that SPICE1 knockdown significantly accelerated FASN protein degradation over time (Fig. 3G, H). The degradation of FASN induced by SPICE1 knockdown was largely rescued by MG132 but not by chloroquine (CQ) (Fig. 3I). Additionally, silencing SPICE1 significantly increased the ubiquitination levels of the FASN protein, whereas SPICE1 overexpression exerted the opposite effect (Fig. 3J; Supplementary Fig. 2C). These findings suggest that SPICE1 regulates the proteasomal degradation of FASN independently of ubiquitination.

Fig. 3
figure 3

SPICE1 interacts with FASN and reduces its ubiquitination level. Gel silver staining analysis revealed that FASN is one of the specific proteins interacting with SPICE1 (A). HEK293T cells were co-transfected with Flag-SPICE1 and HA-FASN, and the cell lysates underwent co-immunoprecipitation and western blotting analyses (B). Endogenous co-immunoprecipitation was performed in 143B and HOS cells to analyze the relationship between SPICE1 and FASN (C). Colocalization of SPICE1 and FASN in 143B and HOS cells (D). We created a diagram of SPICE1 and its truncated mutants to map the FASN-binding domain, followed by a co-immunoprecipitation assay to confirm our findings (E). HOS and 143B cells were harvested to evaluate the protein levels of SPICE1 and FASN after either stably overexpressing or silencing SPICE1 (F). HOS and 143B cells with stably silenced SPICE1 were treated with 50 μg/ml cycloheximide for an indicated time interval, followed by western blotting analyses (G, H). HOS and 143B cells with stably silenced SPICE1 were treated with 20 μM MG132 or 100 μM chloroquine for 4 h, followed by western blotting analyses (I). HOS and 143B cells with stably silenced SPICE1 were treated with 20 μM MG132 for 4 h. We then conducted co-immunoprecipitation and western blotting analyses to detect the ubiquitination level of the FASN protein (J). The data was presented as means ± SD. The experiment was conducted three times independently, and all trials produced similar results

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USP10 deubiquitinates and stabilizes FASN

As demonstrated in Fig. 3, SPICE1 inhibits the ubiquitination of FASN, leading to increased FASN protein levels. Given that SPICE1 lacks structural features characteristic of deubiquitinating enzymes, we hypothesized the involvement of a related ubiquitination enzyme [16]. To investigate this, we conducted mass spectrometry analysis on proteins interacting with FASN during SPICE1 overexpression, identifying 173 proteins with altered binding to FASN (termed PBF) (Fig. 4A). We then compared these proteins with ubiquitination-related enzymes from the UbiBrowser dataset [17], identifying USP10 as a potential deubiquitinating enzyme that may enhance its interaction with FASN during SPICE1 overexpression (Fig. 4A and Supplementary Excel 2). To validate these findings, we co-transfected HEK293T cells were with Myc-USP10 and HA-FASN plasmids and performed exogenous immunoprecipitation assays. As shown in Fig. 4B, C, either immunoprecipitated Myc (USP10) or HA (FASN), the other protein was co-precipitated, confirming that USP10 interacts with FASN. Furthermore, endogenously immunoprecipitated USP10 or FASN in HOS and 143B cells also showed that FASN or USP10 were also co-precipitated (Fig. 4D). Besides, immunofluorescence co-stained USP10 and FASN in HOS and 143B cells showed they co-localize in spatial location (Fig. 4E). Further exploration of this interaction involved constructing three truncated USP10 variants for co-immunoprecipitation experiments, as described in a previous study [18], revealing that the C-terminal region (amino acids 400–798) of USP10 interacts with FASN (Supplementary Fig. 2 D, E).

Fig. 4
figure 4

USP10 deubiquitinates FASN. USP10 was screened using a Venn diagram that compared proteins with altered binding to FASN after SPICE1 overexpression and related ubiquitination enzymes from the UbiBrowser platform (A). HEK293T cells were co-transfected with Myc-USP10 and HA-FASN, followed by co-immunoprecipitation and western blotting analyses to detect the interactions between USP10 and FASN (B, C). Endogenous co-immunoprecipitations were performed on 143B and HOS cells to detect the interactions between USP10 and FASN (D). Immunofluorescence experiments demonstrated colocalization of USP10 with FASN in 143B and HOS cells (E). The Western blotting assay demonstrated that the knockdown of USP10 caused a reduction in FASN protein levels in OS cells (F). Experiments involving cycloheximide (CHX) demonstrated that reducing the levels of USP10 increased the breakdown of the FASN protein (G–J). 143B and HOS cells with stably silenced USP10 were treated with 20 μM MG132 for 4 h, followed by co-immunoprecipitation and western blotting analyses to detect the ubiquitination level of FASN (K). HEK293T cells were co-transfected with either sh-Ctrl or sh-USP10 along with HA-Ub (WT, K48, or K63) plasmids. We then performed co-immunoprecipitation and western blotting analyses on the cell lysates to assess the ubiquitination level of FASN. The analysis indicated that USP10 catalyzed the deubiquitination of FASN linked to Lys 48 ubiquitin chains (L). HEK293T cells were co-transfected with HA-FASN and Myc-USP10 plasmids (Vector, WT, or C424A). The cell lysates were then analyzed using co-immunoprecipitation and western blotting methods to determine the ubiquitination level of FASN. The results showed that the C424A point mutation in USP10 eliminated its ability to deubiquitinate FASN (M). HEK293T cells were co-transfected with either Vector or Myc-USP10 along with HA-FASN plasmids, which included wild-type (WT) and point mutants. We then conducted co-immunoprecipitation and western blotting analyses to measure FASN ubiquitination levels. The results showed that overexpression of USP10 increased the ubiquitination levels of the FASN K1769R and K1925R mutants (N, O). The experiment was repeated three times independently with similar results. *PBF: Proteins exhibiting altered binding to FASN upon SPICE1 overexpression

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Next, we assessed the impact of USP10 on FASN in OS. Initially, we observed that USP10 knockdown led to a decrease in FASN protein levels in OS cells (Fig. 4F). Additionally, USP10 knockdown accelerated FASN protein degradation, as demonstrated in cycloheximide (CHX) block experiments (Fig. 4G–J). We then examined the effect of USP10 on FASN ubiquitination, finding that USP10 knockdown enhanced FASN protein ubiquitination in OS cells (Fig. 4K). Further ubiquitination experiments revealed that USP10 catalyzed the deubiquitination of FASN linked to Lys 48 ubiquitin chains (Fig. 4L). Importantly, a C424A point mutation in USP10 abolished its deubiquitinating activity [19], rendering it incapable of deubiquitinating FASN (Fig. 4M). This underscores the critical role of USP10’s deubiquitinating enzyme activity in the regulation of FASN. Using a ubiquitination site prediction tool [20], we identified 22 potential target sites on the FASN protein for USP10 (Supplementary Excel 3). We constructed mutants at these sites and found that overexpression of USP10 increased the ubiquitination level of the FASN K1769R and K1925R mutants (Fig. 4N, O), indicating that USP10 specifically catalyzes deubiquitination at Lys 1769 and 1925. Collectively, these findings highlight USP10’s role in deubiquitinating and stabilizing FASN.

SPICE1 promotes deubiquitination of FASN by enhancing the interaction of FASN with USP10

To determine whether the deubiquitination of FASN by USP10 is dependent on SPICE1, we transfected HEK293T cells with varying amounts of Flag-SPICE1 alongside equal amounts of HA-FASN and Myc-USP10 plasmids. We observed that the interaction between USP10 and FASN progressively increased with SPICE1 overexpression (Fig. 5A, B). Conversely, SPICE1 knockdown reduced the interaction between USP10 and FASN (Fig. 5C, D). As shown in Fig. 3E, the CC1 domain of SPICE1 is essential for its interaction with FASN. To investigate whether this domain is also required for the interaction between USP10 and FASN, as well as for the regulation of FASN ubiquitination levels, we evaluated SPICE1-knockdown cells reconstituted with SPICE1 lacking the CC1 domain. The results confirmed that the CC1 domain of SPICE1 is critical for facilitating the interaction between USP10 and FASN and for modulating FASN ubiquitination levels (Fig. 5E). Additionally, we utilized the HDOCK server to model the 3D structure of SPICE1 (Q8N0Z3) bound to FASN (A0A0U1RQF0), revealing that amino acids 377, 379, and 381 in the N-terminal region of SPICE1 are likely critical for its interaction with FASN (Supplementary Fig. 3A-C). Following this, we synthesized two peptides: SPICE1 (375–386), corresponding to amino acids 375–386, and SCpep, a scrambled variant used as a negative control. As anticipated, SPICE1 (375–386) effectively disrupted the interaction between SPICE1 and FASN, also reducing USP10 binding to FASN compared to SCpep (Fig. 5F). Furthermore, SPICE1 (375–386) promoted FASN ubiquitination more efficiently than SCpep (Fig. 5G). Notably, USP10 knockdown reversed the decrease in FASN ubiquitination caused by SPICE1 overexpression in both OS and HEK293T cells (Fig. 5H, I). In summary, these findings suggest that SPICE1 enhances the interaction between USP10 and FASN, and that the deubiquitination of FASN by USP10 is reliant on SPICE1.

Fig. 5
figure 5

SPICE1 enhances the interaction of FASN with USP10. HEK293T cells were co-transfected with HA-FASN, Myc-USP10, and varying concentrations of Flag-SPICE1. We then subjected the cell lysates to co-immunoprecipitation and western blotting analyses to examine the interactions between USP10 and FASN. The analysis revealed that the interaction between USP10 and FASN strengthened as SPICE1 was increasingly overexpressed (A, B). We conducted co-immunoprecipitation and western blotting analyses on HOS and 143B cells with stable SPICE1 silencing, which demonstrated a significant reduction in the interaction between USP10 and FASN upon SPICE1 knockdown (C, D). SPICE1-knockdown cells were reconstituted with either SPICE1 lacking the CC1 domain or wild-type (WT) SPICE1. The results confirmed that the CC1 domain of SPICE1 is essential for facilitating the interaction between USP10 and FASN, as well as for modulating the ubiquitination levels of FASN (E). HOS and 143B cells were treated with either the SPICE1 peptide (375–386) or SCpep. After treatment, cell lysates underwent co-immunoprecipitation and western blotting analyses. The findings revealed that SPICE1 (375–386) effectively disrupted the interaction between SPICE1 and FASN. Additionally, it reduced the binding of USP10 to FASN when compared to SCpep (F). HOS and 143B cells were treated with either SPICE1 peptide (375–386) or SCpep. We performed co-immunoprecipitation and western blotting analyses on the cell lysates to assess FASN ubiquitination. The findings revealed that SPICE1 (375–386) more effectively enhanced FASN ubiquitination compared to SCpep (G). HEK293T cells were co-transfected with HA-FASN, Flag-SPICE1, and sh-USP10 plasmids. The cells were then treated with 20 μM MG132 for 4 h. We performed co-immunoprecipitation and western blotting analyses on the cell lysates to assess FASN ubiquitination. The results indicated that knocking down USP10 reversed the reduction in FASN ubiquitination caused by SPICE1 overexpression (H). HOS and 143B cells stably overexpressed SPICE1 and silenced USP10, were treated with 20 μM MG132 for 4 h. Co-immunoprecipitation and western blotting analyses were then performed to detect FASN ubiquitination. The results showed that the knockdown of USP10 reversed the decrease in FASN ubiquitination caused by SPICE1 overexpression (I)

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SPICE1 promotes OS cell proliferation and tumor growth via the USP10/FASN axis

Given the role of USP10/FASN in mediating SPICE1’s oncogenic effects in OS, we investigated the impact of USP10 or FASN rescue on the cellular phenotypes induced by alterations in SPICE1 expression. The silencing of USP10 or FASN in OS stable cells with SPICE1 overexpression was confirmed through western blotting assays (Supplementary Fig. 2F, G). The knockdown of USP10 or FASN attenuated the positive effects of SPICE1 overexpression on cell proliferation, as assessed by CCK-8, colony formation, and EdU assays (Fig. 6A–G). In a mouse xenograft model using 143B cells, in vivo upregulation of SPICE1 significantly promoted tumor growth, while the knockdown of USP10 or FASN reversed this effect (Fig. 6H–J). Collectively, these data suggest that SPICE1 regulates cell proliferation and tumor growth by modulating FASN through the USP10 pathway (Fig. 7).

Fig. 6
figure 6

SPICE1 promotes OS cell proliferation and tumor growth via the USP10/FASN axis. HOS and 143B cells with stably overexpressed SPICE1 and silenced USP10 or FASN were subjected to CCK8 assays (A, B), colony formation assays (C, D), and EdU assays (E–G). Growth of subcutaneous transplanted tumors in nude mice (H). Tumor weight at the end of the experiment (I). Image of exfoliated tumors (J). Data were presented as means ± SD. *P < 0.05; **P < 0.01; ***P < 0.001; by two-tailed Student’s t-test

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Fig. 7
figure 7

Proposed model for SPICE1 promoting the progression of OS by enhancing USP10 to deubiquitinate and stabilize FASN. SPICE1 is highly expressed in osteosarcoma cells, where it binds to FASN and promotes the association of USP10 with FASN, enhancing the deubiquitination and stabilization of FASN, which in turn facilitates the progression of OS

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Discussion

Osteosarcoma (OS) represents a highly aggressive bone malignancy that predominantly affects the pediatric and adolescent populations [21]. Despite significant advancements in treatment modalities, the prognosis for patients diagnosed with OS remains unsatisfactory [22], highlighting the pressing need for the identification of novel biomarkers and therapeutic targets. Current investigations have elucidated several genes and signaling pathways implicated in OS; however, a thorough understanding of the underlying molecular mechanisms remains elusive [23].

As a protein associated with centrosomes and spindle apparatus, SPICE1 is integral to the regulation of cell mitosis. Dysregulation of SPICE1 can lead to functional impairments in both centrosomes and chromosomes, which are closely linked to tumor initiation and progression [24]. This suggests a potential role for SPICE1 in oncogenesis, yet its specific contributions and mechanisms in cancer pathophysiology are not fully elucidated.

In our study, we observed that SPICE1 is overexpressed in OS tissues and cell lines, correlating with poorer patient outcomes. Additionally, SPICE1 was shown to enhance OS cell proliferation in vitro and tumor growth in vivo, indicating its function as a novel oncogene in OS. To our knowledge, this study is the first to report the involvement of SPICE1 in promoting OS cell proliferation. To elucidate the molecular mechanisms at play, we performed immunoprecipitation of SPICE1 from OS cells followed by LC–MS/MS analysis, which identified FASN as a binding partner of SPICE1. This interaction was subsequently validated through co-immunoprecipitation and co-immunofluorescence assays. Notably, our findings revealed that SPICE1 increases FASN protein levels without affecting its mRNA expression, suggesting a regulatory role for SPICE1 at the post-translational modification level. The reduction in FASN levels following SPICE1 knockdown was effectively reversed by MG132 treatment, indicating that SPICE1 modulates FASN stability through the ubiquitin–proteasome pathway.

Lipid metabolism is critical in cancer biology, providing essential energy, signaling molecules, and membrane components necessary for cellular proliferation and migration [25,26,27,28]. FASN serves as a pivotal regulator of lipid metabolism, catalyzing de novo fatty acid synthesis to meet the heightened energy and biosynthetic demands of tumor cells [29, 30]. Overexpression of FASN has been documented across various malignancies, including breast, cervical, and prostate cancers [31,32,33,34]. and is instrumental in promoting cancer progression through modulation of lipid metabolism. Our previous research established a positive correlation between FASN expression and Ki-67 protein levels, alongside its association with pulmonary metastasis in OS [13]. Furthermore, FASN has been implicated in facilitating OS growth and metastasis by mediating resistance to anoikis via the ERK/Bcl-xL signaling pathway [15]. The inhibitory effects of α-linolenic acid, a known FASN inhibitor, on OS cell proliferation and invasion through the induction of endoplasmic reticulum stress further underscore the significance of FASN in OS progression [35].

In this study, we elucidated the interaction between SPICE1 and FASN, demonstrating that SPICE1 stabilizes FASN by inhibiting its ubiquitin-mediated degradation. This novel finding sheds light on the intricate regulation of FASN stability in OS and suggests a potential avenue for future therapeutic interventions. Various regulatory mechanisms govern FASN expression and activity, including interactions with diverse proteins. Sterol regulatory element-binding proteins, which enhance FASN expression by stimulating its promoter activity, exemplify transcriptional regulation [36]. Additionally, emerging evidence indicates that post-translational modifications of FASN are crucial for its functionality. For instance, Jin et al. demonstrated that inhibition of HER2 kinase activity diminishes FASN tyrosine phosphorylation and enzymatic activity, thereby curtailing breast cancer cell invasion [37]. Moreover, FASN can be targeted for degradation via the ubiquitin–proteasome pathway, facilitated by the interaction with FBXW7, which promotes its ubiquitination and subsequent degradation [38]. USP14, another deubiquitinating enzyme, stabilizes FASN by removing ubiquitin molecules from target proteins [39]. Given the absence of a deubiquitination domain in SPICE1, it is plausible that SPICE1 regulates FASN stability through its interaction with a specific deubiquitinating enzyme.

Through SPICE1 overexpression and subsequent LC–MS/MS analysis, we identified USP10 as a key deubiquitinase that enhances its binding to FASN. USP10, a member of the USP family of deubiquitinating enzymes, is characterized by its classic USP domain and is recognized for its deubiquitination function [40]. USP10 has been implicated in negatively regulating proteasomal activity across various cancers [18, 41,42,43]. USP10 can remove ubiquitin from ubiquitinated PTEN, thereby reversing its regulation mediated by ubiquitination [44]. Furthermore, USP10 is involved in the regulation of p53 through deubiquitination, which results in the stabilization of p53 [45].

To ascertain whether USP10 stabilizes FASN via deubiquitination, we conducted a series of experiments. Co-immunoprecipitation and immunofluorescence assays confirmed the interaction between USP10 and FASN. Our assessments of protein stability and ubiquitination indicated that USP10 contributes to FASN stabilization by preventing its degradation through deubiquitination. Furthermore, we observed that SPICE1 knockdown resulted in diminished binding affinity between USP10 and FASN. Notably, SPICE1 overexpression led to decreased FASN ubiquitination, which was restored upon USP10 knockdown. Collectively, these findings suggest that SPICE1 inhibits FASN ubiquitination and subsequent degradation in a USP10-dependent manner, unveiling a novel regulatory mechanism in protein ubiquitination. Besides, this study demonstrates that SPICE1 increases the interaction between FASN and USP10. Furthermore, peptides that prevent SPICE1 from binding to FASN decrease this interaction. This reduction may result from a conformational change in FASN caused by its binding to SPICE1, which enhances its interaction with USP10. Therefore, additional experimental studies are required to elucidate the specific mechanism involved.

While our findings provide valuable insights into the molecular mechanisms underlying OS progression, we acknowledge certain limitations that warrant consideration. Firstly, our study primarily focused on the expression levels and functional roles of SPICE1 both in vitro and in vivo. Although we observed a significant correlation between SPICE1 overexpression and poor patient prognosis, the study was limited by the relatively small sample size of the clinical tissues analyzed. Future studies should aim to include a larger cohort of OS patients to validate our findings and assess the generalizability of SPICE1 as a prognostic biomarker. Secondly, while we established a mechanistic link between SPICE1, FASN, and USP10, the precise molecular pathways and regulatory networks involving these proteins remain to be fully elucidated. Further investigations are needed to explore the downstream effects of SPICE1 on other signaling pathways and cellular processes in OS. Additionally, the role of other post-translational modifications on FASN and their potential interplay with SPICE1 and USP10 should be examined to provide a more comprehensive understanding of the regulatory mechanisms at play. Moreover, the development of specific inhibitors targeting the SPICE1/USP10/FASN signaling axis presents a promising therapeutic avenue. However, the design and testing of such inhibitors will require extensive preclinical studies to evaluate their efficacy, specificity, and potential off-target effects in OS models. Future research should also focus on the feasibility of translating these findings into clinical applications, including the assessment of combination therapies that may enhance treatment outcomes for OS patients.

In conclusion, our research has pioneered the identification and validation of SPICE1 overexpression in OS, which correlates with poor patient prognosis. Our findings further elucidate the role of SPICE1 in promoting OS cell proliferation. Mechanistically, SPICE1 inhibits FASN ubiquitination and degradation, thereby stabilizing and positively regulating FASN expression, which contributes to the progression of OS. Additionally, we confirmed that SPICE1 stabilizes FASN by recruiting USP10, thereby promoting OS cell proliferation. This novel SPICE1/USP10/FASN signaling pathway represents a promising therapeutic target for combating OS.

Availability of data and materials

The data from this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the National Natural Science Foundation of China, the Jiangxi Province Natural Science Foundation, Jiangxi's major science and technology R&D projects, and the “Double Thousand Plan” for their financial support of this research.

Funding

This work was partially funded by Grants from the National Natural Science Foundation of China (82360543), the Natural Science Foundation of Jiangxi Province (20232ACB216011, 20232ACB206043), the major science and technology R&D projects of Jiangxi Province (20213AAG01013), and the “Double Thousand Plan” of Jiangxi Province.

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Author notes

  1. Weilai Tong, Xinsheng Xie and Zhiguo Shu contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopedic Surgery, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China

    Weilai Tong, Zhiguo Shu, Jiangbo Nie, Feng Yang, Zhili Liu & Jiaming Liu

  2. Jiangxi Provincial Key Laboratory of Spine and Spinal Cord Diseases, Nanchang, 330006, People’s Republic of China

    Weilai Tong, Xinsheng Xie, Zhiguo Shu, Jiangbo Nie, Feng Yang, Zhili Liu & Jiaming Liu

  3. Medical Innovation Center, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China

    Xinsheng Xie & Xianhe Yang

  4. Postdoctoral Innovation Practice Base, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China

    Weilai Tong

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Contributions

W.T., X.X., and Z.S. conducted experiments and analyzed the data. The manuscript was written by W.T. and X.X. Statistical analysis was supervised by J.N., and F.Y. provided materials and reviewed the manuscript. X.Y. provided advice on some experiments. The study was planned and overseen by Z.L. and J.L.

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Correspondence to Zhili Liu or Jiaming Liu.

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Tong, W., Xie, X., Shu, Z. et al. SPICE1 promotes osteosarcoma growth by enhancing the deubiquitination of FASN mediated by USP10. J Transl Med 23, 220 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12967-025-06248-1

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Journal of Translational Medicine

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