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DLAT is involved in ovarian cancer progression by modulating lipid metabolism through the JAK2/STAT5A/SREBP1 signaling pathway

Cancer Cell International volume 25, Article number: 25 (2025) Cite this article

Abstract

Background

Ovarian cancer (OC) remains a lethal gynecological malignancy with an alarming mortality rate, primarily attributed to delayed diagnosis and a lack of effective treatment modalities. Accumulated evidence highlights the pivotal role of reprogrammed lipid metabolism in fueling OC progression, however, the intricate underlying molecular mechanisms are not fully elucidated.

Methods

DLAT expression was assessed in OC tissues and cell lines by immunohistochemistry, western blot and qRT-PCR analysis. The effects of DLAT silencing on changes in lipid metabolism, cell viability, migration, and invasion were examined in SKOV3 and OVCAR3 cells using CCK-8, colony formation, Transwell migration and invasion, and wound-healing assays. GSEA analysis was used to examine the relationship between DLAT and lipid metabolism-related enzymes. Rescue experiments in which SREBP1 was overexpressed in DLAT-silenced cells were carried out. Western blot analysis was performed to determine whether the JAK2/STAT5 signaling pathway was involved in DLAT-regulated SREBP1 expression. Commercially available triglyceride and cholesterol detection kits, as well as Nile Red and Oil red O staining were used to measure lipid metabolism. A subcutaneous tumor model was established in BALB/c mice to confirm the role of the DLAT/SREBP1 axis in OC growth and metastasis in vivo.

Results

DLAT expression was significantly upregulated in OC patient tissue and associated with poor prognosis. Silencing DLAT reduced lipid content and impaired OC cell proliferation, migration, and invasion. DLAT upregulated SREBP1 expression via the JAK2/STAT5 signaling pathway, enhancing expression of fatty acid synthesis enzymes and altering lipid metabolism. SREBP1 was essential for DLAT-dependent OC cell growth and metastasis both in vitro and in vivo.

Conclusion

This study uncovers a novel DLAT/JAK2/STAT5/SREBP1 axis that reprograms lipid metabolism in OC, providing insights into metabolic vulnerabilities and potential therapeutic targets for OC treatment.

Introduction

Ovarian cancer (OC) is the eighth most common cancer in women worldwide and a leading cause of gynecological cancer-related deaths [1, 2]. Even with significant advances in therapeutic strategies for OC, including surgery, radiotherapy, chemotherapy and more recently the development of targeted drug delivery systems [3,4,5], the 5-year survival rate for OC patients remains low. The low survival rate has been attributed to the misdiagnosis of non-specific symptoms during the early stages of the disease, which results in delayed diagnosis, such that patients are already in Stage 3 or 4 OC when finally diagnosed [6,7,8]. The limited success of current therapeutic options, in part due to the development of chemoresistance [9], has increased the need to develop novel and innovative strategies to treat OC patients.

Circadian rhythms play a fundamental role in regulating various physiological processes, including lipid metabolism and hormonal homeostasis. The molecular clock machinery tightly controls lipid synthesis, storage, and transport throughout the day-night cycle, which is essential for maintaining metabolic homeostasis [10, 11]. Disruption of circadian rhythms has been associated with metabolic disorders and cancer development, suggesting a potential link between circadian regulation of lipid metabolism and tumor progression [12, 13]. In cancer cells, this intricate temporal control of lipid metabolism is often dysregulated, contributing to altered metabolic patterns that support tumor growth.

Recently, targeting lipid metabolism in tumor cells has become a major focus in the development of potential therapeutic strategies for multiple types of cancer [14,15,16] including cervical cancer [17] and advanced prostate cancer [18]. Lipid metabolism regulates numerous physiological processes, including cell growth, proliferation, differentiation, apoptosis, migration and invasion. Reprogramming of lipid metabolism is a hallmark of cancer with increased fat uptake, storage and production providing tumor cells with energy, biological membrane components and signaling molecules that promote the rapid growth, invasion, and migration of tumors [19,20,21,22]. Although reprogramming of fatty acid metabolism has been shown to play a crucial role in OC progression [23], the underlying mechanisms remain unclear.

Sterol regulatory element-binding proteins (SREBPs) are important transcription factors that regulate lipid metabolism by controlling the expression of key genes required for cholesterol biosynthesis, lipid homeostasis, and fatty acid synthesis including ATP citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD) [24, 25]. Upregulation of SREBPs has been reported in various cancers including endometrial cancer [26], breast cancer [27] and hepatocellular carcinoma (HCC) [28]. Targeting SREBP1-mediated lipogenesis has been proposed as a potential therapeutic strategy for multiple cancer types [29, 30]. For example, cinobufotalin has been shown to suppress HCC proliferation through inhibition of SREBP1-mediated lipogenesis, where it interferes with SREBP1 binding to sterol regulatory elements (SREs) and consequently reduces the expression of lipogenic enzymes [31]. However, the role of SREBP1 in OC has not been studied extensively.

Dihydrolipoamide S-transferase (DLAT), a key enzymatic subunit of the pyruvate dehydrogenase complex (PDC), has been implicated in the regulation of fatty acid synthesis in various cancers. DLAT is expressed in the inner mitochondrial membrane and plays a critical role in the breakdown of pyruvate into acetyl-CoA and the generation of NADH [32]. DLAT has been shown to be upregulated in gastric cancer [33], HCC [34], intrahepatic cholangiocarcinoma [35], and esophageal and lung cancer [36]. However, the precise roles of DLAT in cancer remain elusive, and the function of DLAT in OC has not been examined.

Here, we show that DLAT is overexpressed in OC and correlates with tumor stage and poor prognosis. DLAT expression led to increased SREBP1 expression via the JAK2/STAT5 pathway, which modified lipid metabolism by increasing FASN expression. In vivo, DLAT promoted OC cell growth and metastasis in a SREBP1-dependent manner. Together, our results demonstrate that the DLAT/JAK2/STAT5/SREBP1 axis is critical for OC and identifies this pathway as a potential target to treat OC.

Materials and methods

Patients and specimens

OC tumor tissue and paired paracancerous tissue were collected from 70 patients, who attended the Obstetrics & Gynecology Hospital of Fudan University from 2021 to 2024. The inclusion criteria were: (1) histologically confirmed primary epithelial ovarian cancer; (2) no prior chemotherapy or radiotherapy; (3) complete clinical and pathological data available. Patients were excluded if they had: (1) other concurrent malignancies; (2) severe systematic diseases; or (3) received neoadjuvant therapy. Paracancerous tissue was collected at least 2 cm away from the tumor margin. This study was approved by the Ethics Committee of Hospital of Fudan University, and written informed consent was obtained from all patients.

Cell lines and cell culture

Normal human ovarian epithelial cells (IOSE-80) and human ovarian cancer epithelial cell lines (A2780, SKOV3, OVCAR3 and CAOV3) were obtained from the Stem Cell Bank of the Chinese Academy of Sciences (Shanghai, China). IOSE80 and SKOV3 cells were cultured in RPMI-1640 (Gibco, USA) containing 10% fetal bovine serum (FBS) (ExCell Bio, China) and 1% penicillin/streptomycin (P/S) (NCM Biotech, China). OVCAR3 cells were cultured in RPMI-1640 containing 20% FBS and 1% PS. A2780 and CAOV3cells were cultured in Dulbecco’s modified Eagle medium (DMEM) (Gibco) containing 10% FBS and 1% PS. All cell lines were cultured at 37 °C in a humidified atmosphere of 5% CO2.

Immunohistochemistry (IHC)

Tumor and paired paracancerous tissue samples were fixed in 10% neutral buffered formalin and stored in 70% ethanol at 4 °C. Paraffin-embedded tissues were sliced into 4-µm thick sections. Following deparaffinization, rehydration and antigen retrieval, sections were blocked in 5% BSA blocking solution for 30 min, then incubated with primary antibodies against DLAT (ab110332, Abcam, 1:1,000, UK), SREBP1 (14088-1-AP, Proteintech, 1:100, USA) or Ki-67 (ab15580, Abcam, 1:200) antibodies overnight at 4 °C. After washing, sections were incubated with horseradish peroxidase (HRP)-conjugated secondary antibodies (Thermo Fisher Scientific, USA) for 1 h at 25 °C. Sections were washed, incubated with 3,3’-diaminobenzidine (DAB) for 10 min to achieve the desired staining intensity, then counterstained with hematoxylin for 1–2 min for visualization of the nuclei. Samples were visualized by light microscopy.

Western blot analysis

Total protein was extracted from cells and tissue samples using ice-cold RIPA buffer containing protease and phosphatase inhibitors (Cell Signaling Technology, USA). Protein quantification was carried out using a BCA Protein Assay Kit (Thermo Fisher Scientific). For each sample, 20–30 µg of total protein was loaded and separated by 10% SDS-PAGE and transferred to PVDF membranes. Membranes were blocked with 5% skim milk in Tris-buffered saline containing Tween-20 (TBST) at room temperature for 1 h, then incubated with primary antibodies at 4 °C overnight. Membranes were washed, then incubated with HRP-conjugated secondary antibodies for 1 h at room temperature. Protein bands were visualized using ECL Kits (Thermo Fisher Scientific). Protein band densities were quantified using Image Lab software (Bio-Rad, Hercules, CA, USA). The following primary antibodies were used: DLAT (ab110332, Abcam, 1:1,000), FASN (ab128870, Abcam, 1:1,000), ACC (ab109368, Abcam, 1:1,000), ACLY (ab40793, Abcam, 1:2,000), SCD (ab236868, Abcam, 1:1,000), SREBP1 (14088-1-AP, Proteintech, 1:10,000), SREBP2 (ab30682, Abcam, 1:1,000), chREBP (ab92809, Abcam, 1:1,000), p-JAK2 (#3776, Cell Signaling, 1:10,000), JAK2 (#3230, Cell Signaling, 1:10,000), p-STAT5 (#4322, Cell Signaling, 1:10,000), and STAT5 (#25656, Cell Signaling, 1:10,000). GAPDH (10494-1-AP, Proteintech, 1:50,000) was used as the loading control.

Quantitative real-time PCR (qRT-PCR)

Total RNA was extracted from cells and tumor tissue samples using TRIzol Reagent (Thermo Scientific, USA). qRT-PCR was carried out using the PrimeScript RT Reagent Kit (TaKaRa, Japan) and QX100 Droplet Digital PCR system (Bio-Rad). GAPDH was used as the internal control. Relative expression levels of each gene were calculated using the 2−△△Ct method. The specific primer sequences used are in Table 1.

Table 1 Primers used in qRT-PCR analysis
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Overexpression and knockdown of target genes

Lentiviral-based small hairpin RNA (shRNA) targeting DLAT (target sequence sh-DLAT#1: 5’-GGTTATTGCACAGCGATTAAT-3’; sh-DLAT#2: 5’-CAACCGAAGTAACAGATTTAA-3’) and control sh-NC (5’-CATAACGGCTATCGAGTTCAGT-3’) were purchased from GenePharma (Shanghai, China). The empty vector and SREBP1 overexpression lentivirus were ordered from GeneCopoeia (USA). Lentiviruses were infected into SKOV3 and OVCAR3 cell lines with an MOI 10 plus 5 mg/ml polybrene for 48 h. Cells were then selected for 2 weeks using puromycin (2 µg/ml, Selleck Chemicals) to produce a stable cell line for subsequent assays.

CCK-8 assay

The CCK-8 assay (Solarbio, Beijing, China) was used to assess cell proliferation. Briefly, SKOV3 and OVCAR3 cells were seeded into 96-well plates (3 × 103 cells/well) in 200 µl culture medium. At the indicated time points (0 h, 24 h, 48 h, 72 h, and 96 h), the supernatant was removed and 10 µl CCK-8 reagent in 100 µl medium was added to each well. The plates were incubated for 2 h in the dark at 37 °C. The absorbance was read at 450 nm using a microplate reader (BioTek, USA). Experiments were carried out in triplicate.

Colony-formation assay

Cells (1 × 103 cells/well) were plated into 6-well plates and cultured for 2 weeks. Colonies were fixed in 4% paraformaldehyde, stained with 1% crystal violet (Sangon Biotech, China) and the number of colonies was counted. Experiments were carried out in triplicate.

5-Ethynyl-2-deoxyuridine (EdU) incorporation assay

The EdU incorporation assay was carried out using the Cell-Light EdU Apollo488 In Vitro Imaging Kit (RiboBio, China) according to the manufacturer’s instructions. Briefly, SKOV3 and OVCAR3 cells were cultured overnight in RPMI-60 medium. The next day, cells were incubated with EdU for 2 h at 37 °C, then fixed in 4% paraformaldehyde. Following permeabilization with 0.5% Triton X-100, cells were stained with Apollo 488 for 30 min. Nuclei were stained with Hoechst 33,342 for 30 min. Samples were visualized by fluorescence microscopy. All experiments were performed in triplicate.

Transwell migration assay

Cell migration and invasion were assessed using the 24-well Transwell chamber system (Corning, USA). For the invasion assay, upper chambers were first coated in 40 µl Matrigel (BD Biosciences). Briefly, SKOV3 and OVCAR3 cells were seeded into the upper chamber in serum-free media. Media containing 20% FBS was placed in the lower chamber. Cells were incubated at 37oC for 24 h for the migration assay and for 48 h for the invasion assay. Non-migrating cells were removed from the upper side of the membrane with a cotton swab. Samples were then washed twice with PBS and fixed in formaldehyde for 10 min. Next, samples were washed three times with water, and stained with 0.1% crystal violet for 30 min at room temperature. The number of cells that migrated into the lower chamber or invaded through the Matrigel into the lower chamber were visualized, imaged, and counted using an inverted microscope (magnification, 100×). The number of migrated or invaded cells in each field was counted using ImageJ software (NIH, USA) The average number of cells from the five fields was calculated for each experimental group.

Wound-healing assay

SKOV3 and OVCAR3 cells were seeded into 6-well plates (4 × 105 cells/well) and cultured to 80% confluency. The cellular monolayer was scraped using a 200 µL pipette tip to create a uniform wound. Non-adherent cells were removed by washing with PBS, and fresh serum-containing media was added. Images were captured at 0 h and 24 h at three random positions along each scratch using an inverted microscope (100× magnification). The area of migrated cells was measured using ImageJ software (NIH, USA). For each group, the migrated cell area was normalized to the control group (sh-NC) to obtain the relative area of migrated cells. All experiments were performed in triplicate.

Triglyceride and cholesterol assays

Intracellular and intratumoral triglyceride and cholesterol levels were measured using kits purchased from Applygen Technologies Inc. (Beijing, China) according to the manufacturer’s instructions. Values were normalized to cellular protein. The protein concentration in the resulting lysates was determined using the BCA Protein Assay Kit (Thermo Scientific).

Nile red staining

Nile red staining was used to detect intracellular lipid droplets in tissue and cell samples. Briefly, cells were fixed in 4% paraformaldehyde, then incubated with 5 µg/ml Nile red solution (MCE, USA) for 30 min. Nuclei were counterstained with Hoescht.

Oil red O staining

Oil red O staining was used to detect lipid content. Briefly, fixed samples were washed in running tap water for 1–10 min, then rinsed with 60% isopropanol. Samples were stained with freshly prepared Oil red O working solution (Sigma-Aldrich, USA) for 15 min. After rinsing in 60% isopropanol, nuclei were stained using hematoxylin solution (Sangon Biotech).

Bioinformatic analysis

OC tissue mRNA expression data were obtained from The Cancer Genome Atlas (TCGA) database. Correlations between the expression of DLAT and other genes were determined using Pearson correlation analysis.

Subcutaneous tumor model in mice

Male 4-week-old BALB/c mice were obtained from Shanghai SLAC Laboratory Animal Co., Ltd. (Shanghai, China) and randomly assigned to the following experimental groups (6 mice/group): sh-NC, sh-DLAT, and sh-DLAT + oeSREBP1. SKOV3 and OVCAR3 cells (5 × 106), transduced with sh-NC, sh-DLAT and sh-DLAT + oeSREBP1 lentiviruses, were subcutaneously injected into nude mice to induce tumor formation. Tumor diameters were measured every four days by measuring the longest diameter (length) and shortest diameter (width) using digital calipers. Tumor volume was calculated using the formula: V = (length × width²)/2. All measurements were performed by two independent researchers who were blinded to the experimental groups. After 28 days, mice were anesthetized with a lethal dose of pentobarbital (100 mg/kg) and humanely killed. Tumor tissue samples were collected and subjected to IHC analysis with antibodies against DLAT, SREBP1, and Ki-67. Oil red O staining and measurement of triglyceride and cholesterol levels were also performed on the samples. All experiments were approved and carried out according to the guidelines of the Ethics Committee of the Hospital of Fudan University.

Statistical analysis

Data analysis was conducted using SPSS 19.0 (SPSS, Inc., Chicago, IL, USA) and GraphPad Prism 9.0 (San Diego, CA, USA) was used to analyze the data from this study. Data were shown as mean ± standard deviation (SD). Statistical significance was assessed by Student’s t-test (two groups) and one-way ANOVA with Tukey’s multiple comparisons test (multiple groups). Pearson correlation analysis analyzed the correlations between groups. A p-value less than 0.05 was considered statistically significance.

Results

DLAT is upregulated in OC patient tissue and OC cells and is associated with poor clinical outcome

Analysis of OC tissue data in the TCGA and GTEx databases revealed that DLAT was significantly overexpressed in OC tumor tissue compared to normal tissue (Fig. 1A). qRT-PCR analysis confirmed that DLAT mRNA expression levels were significantly higher in OC tumor tissue samples than normal controls (Fig. 1B). DLAT protein expression levels were also found to be significantly higher in OC tumor tissue samples than normal tissue (Fig. 1C). To determine whether DLAT expression levels were associated with worse clinical outcomes, we next compared DLAT mRNA expression levels in OC stage I-II and OC stage III-IV patients and found significantly higher DLAT expression levels in OC stage II-IV patients than OC stage I-II (Fig. 1D). Western blot analysis (Fig. 1E) and IHC staining (Fig. 1F) of DLAT protein expression levels in 5 paired OC patient tumor tissue samples revealed that DLAT expression levels increased with higher OC tumor stages, suggesting that higher DLAT expression levels were associated with a higher tumor stage and worse clinical outcome. Finally, examination of normal human ovarian epithelial cells (IOSE-80) and various OC tumor cell lines (A2780, SKOV3, OVCAR3, and CAOV3) revealed significantly higher DLAT mRNA (Fig. 1G) and protein (Fig. 1H) expression levels in the OC tumor cell lines. Taken together, our findings indicate that DLAT is upregulated in OC patient tumor tissue and OC cell lines and is associated with poorer clinical outcomes.

Fig. 1
figure 1

DLAT is upregulated in OC patient tissue and OC cells and is associated with poor clinical outcomes. (A) Analysis of OC patient tissue data from the TCGA and GTEx databases revealed upregulation of DLAT mRNA expression levels in OC tumor tissues (n = 376) compared with normal tissues (n = 180) by box plot. (B) qRT-PCR analysis of DLAT mRNA expression levels in 70 paired normal and OC tumor tissue samples. (C) Western blot analysis of DLAT protein expression levels in 7 paired normal and OC tumor tissue samples. (D) qRT-PCR analysis was used to compare DLAT mRNA expression levels in patients with OC stages I-II and OC stages III–IV. (E) Western blot analysis of DLAT protein expression levels in 5 paired normal and OC tumor tissue samples with OC stages I–IV. (F) Representative IHC images showing DLAT staining in 5 paired normal and OC tumor tissue samples with OC stages I–IV. Scale bar = 200 μm. (G) qRT-PCR analysis of DLAT mRNA expression levels in normal human ovarian epithelial cells (IOSE-80) and OC cells (A2780, SKOV3, OVCAR3, and CAOV3), n = 3. (H) Western blot analysis of DLAT protein expression levels in IOSE-80 and OC tumor cells, n = 3. Data are presented as the mean ± SD. ***P < 0.001, **P < 0.01, and *P < 0.05

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DLAT silencing significantly reduces lipid content in OC cells and impairs OC cell proliferation and metastasis in vitro

GSEA analysis of TCGA ovarian cancer dataset revealed that DLAT expression positively correlated with ‘Cell Cycle’ and ‘Sphingolipid Metabolism’ gene signatures (Fig. 2A). Thus, we next examined the effects of DLAT knockdown on lipid content, proliferation and metastasis in the SKOV3 and OVCAR3 cell lines. qRT-PCR and western blot analysis confirmed that DLAT expression levels were significantly reduced following transfection with two shRNAs (sh-DLAT#1 and sh-DLAT#2) (Fig. 2B). Knockdown of DLAT led to a reduction in cellular neutral lipids as measured by Nile Red staining (Fig. 2C). Similarly, the cellular triglyceride (Fig. 2D) and cholesterol (Fig. 2E) content were significantly reduced in DLAT-silenced SKOV3 and OVCAR3 cells. The effects of DLAT knockdown on cell proliferation were next examined using CCK-8, EdU and colony formation assays, and revealed that knockdown of DLAT led to a significant reduction in cell proliferation (Fig. 2F-H). Similarly, DLAT silencing resulted in a significant reduction in OC migration, invasion and wound-healing (Fig. 2I-J). Taken together, these findings suggest that knockdown of DLAT significantly reduces the lipid content in OC cells, as well as impairs OC cellular proliferation and metastasis.

Fig. 2
figure 2

DLAT silencing significantly reduces lipid content in OC cells and impairs OC cell proliferation and metastasis in vitro. (A) GSEA analysis of TCGA ovarian cancer dataset showing positive correlation between DLAT expression and ‘Cell Cycle’ and ‘Sphingolipid Metabolism’ gene signatures. (B) qRT-PCR and western blot analysis were used to confirm the transfection efficiency of two specific DLAT shRNAs (sh-DLAT#1 and sh-DLAT#2) in SKOV3 or OVCAR3 cells. (C-J) SKOV3 or OVCAR3 cells were transduced using sh-NC, sh-DLAT#1, or sh-DLAT#2 lentiviruses. Cells that were not transduced with lentivirus were used as controls. (C) Nile Red staining was used to measure cellular neutral lipids. Nuclei were stained with Hoechst. Scale bar = 50 μm. (D) Triglyceride levels were measured using a commercially available kit. Values were normalized to cellular proteins. Data are presented as mean ± SD and are representative of three independent experiments. (E) Cellular cholesterol content was measured using a commercially available kit. (F) Cell proliferation was assessed using the CCK-8 assay. (G) The EdU assay was used to assess cellular proliferation. Scale bar = 50 μm. (H) The colony formation assay was used to assess colony formation. (I) Transwell migration and invasion assays were used to assess the migratory and invasive abilities of cells. (J) The wound-healing migration assay was used to assess the effects of DLAT knockdown on cellular migration. Scale bar = 100 μm. Data are presented as the mean ± SD, n = 3. Statistical significance was determined by comparing each experimental group to the sh-NC control group. ***P < 0.001, **P < 0.01, and *P < 0.05

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DLAT increases expression of lipid metabolism-related enzymes in OC cells

Next, we sought to determine the relationship between DLAT and lipid metabolism. Analysis of OC patient data from the TCGA database and clinical samples revealed that high DLAT expression levels were correlated with the gene expression of lipid metabolism-related enzymes including FASN, ACLY, ACC1, and SCD1 (Fig. 3A-B). Knockdown of DLAT led to a decrease in FASN, ACLY, ACC1 and SCD1 mRNA and protein (Fig. 3C-D) expression levels in SKOV3 and OVCAR3 cell lines. These findings indicated that DLAT upregulates the expression of lipid metabolism-related enzymes in OC.

Fig. 3
figure 3

DLAT increases the expression of lipid metabolism-related enzymes in OC cells. (A) Correlation analysis between DLAT expression and the expression of lipid metabolism-related enzymes (FASN, ACLY, ACC1, and SCD1) in ovarian cancer patients from the TCGA database. (B) Scatter plot analysis showing the correlation between the mRNA expression levels of DLAT and lipid metabolism-related enzymes in 70 paired normal and OC tumor tissues. (C, D) qRT-PCR and western blot analysis were used to examine the effects of DLAT knockdown on the mRNA and protein expression levels of lipid metabolism-related enzymes in SKOV3 or OVCAR3 cells transduced with sh-NC, sh-DLAT#1, or sh-DLAT#2 lentiviruses. SKOV3 or OVCAR3 cells that were not transduced with lentivirus were used as controls. GAPDH was used as a loading control. Statistical significance was determined by comparing each experimental group to the sh-NC control group. Data are presented as the mean ± SD, n = 3. ***P < 0.001

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DLAT enhances fatty acid synthase expression by upregulating SREBP1

We next sought to determine the role of DLAT in regulating lipid metabolism by examining the effects of DLAT knockdown on the expression of key molecules involved in regulating lipid synthesis including SREBP1, which is involved in regulating fatty acid synthesis, SREBP2, which is involved in regulating cholesterol synthesis, and carbohydrate-responsive element binding protein (chREBP), which is involved in sensing glucose and regulating nutrient homeostasis, especially lipid synthesis. Knockdown of DLAT resulted in a significant reduction in SREBP1 mRNA and protein expression levels, while SREBP2 and chREBP levels remained relatively unaffected (Fig. 4A-B). Scatter plot analysis confirmed that DLAT and SREBP1 were positively correlated in 70 OC tissue samples (Fig. 4C). To further elucidate the relationship between DLAT and SREBP1, we next overexpressed SREBP1 in DLAT-silenced SKOV3 and OVCAR3 cells and found that overexpression of SREBP1 in the absence of DLAT rescued FASN, ACC, ACLY and SCD protein expression levels (Fig. 4D). Overexpression of SREBP1 in DLAT-silenced cells also rescued triglyceride content (Fig. 4E), cholesterol content (Fig. 4F) and neutral lipids (Fig. 4G). Furthermore, we also examined the mRNA expression of lactate dehydrogenase A and B (LDHA/B). Interestingly, neither LDHA nor LDHB showed significant changes in mRNA expression following DLAT knockdown, suggesting that DLAT-mediated metabolic reprogramming might primarily affect lipid metabolism through SREBP1, rather than directly regulating glycolysis at the transcriptional level (Fig. 4H). Together, our findings suggest that DLAT regulates lipid metabolism in OC cells through SREBP1-dependent expression of lipid biosynthetic enzymes.

Fig. 4
figure 4

DLAT enhances FASN expression by upregulating SREBP1. (A-B) The effects of DLAT knockdown on SREBP1, SREBP2, and chREBP mRNA and protein expression levels were examined in OC cells by qRT-PCR and western blot analysis, respectively. SKOV3 or OVCAR3 cells were transduced with sh-NC, sh-DLAT#1, or sh-DLAT#2 lentiviruses. Cells not transduced with lentivirus were used as controls. GAPDH was selected as the internal control. (C) Scatter plot analysis showing the correlation between DLAT and SREBP1 mRNA expression levels in 70 OC tissues. (D-G) SKOV3 or OVCAR3 cells were divided into the following treatment groups: sh-NC, sh-DLAT, sh-DLAT + EV (empty vector) and sh-DLAT + oeSREBP1. (D) Western blot analysis of SREBP1, ACLY, FASN, ACC, and SCD protein expression levels in the indicated treatment groups. GAPDH was used as a loading control. (E-F) Cellular contents of triglyceride (E) and cholesterol (F) were measured in the indicated cells. (G) Nile Red staining was used to measure cellular neutral lipids in the indicated cells. Nuclei were stained with Hoescht (blue). Scale bar = 50 μm. (H) qRT-PCR analysis of LDHA and LDHB mRNA expression levels in SKOV3 and OVCAR3 cells with indicated treatments. Data are presented as the mean ± SD, n = 3. For statistical analysis, comparisons were made between two specific groups: (1) sh-NC versus sh-DLAT to evaluate the effects of DLAT knockdown, and (2) sh-DLAT + EV versus sh-DLAT + oeSREBP1 to assess the rescue effects of SREBP1 overexpression. Ns, no significance, ***P < 0.001, and **P < 0.01

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DLAT upregulates SREBP1 expression and mediates lipid metabolism through the JAK2/STAT5 signaling pathway in OC cells

GSEA analysis of the TCGA ovarian cancer dataset revealed that DLAT expression positively correlated with the JAK-STAT signaling pathway (Fig. 5A). Thus, we next examined the effects of DLAT knockdown on the expression of key JAK2/STAT5 signaling molecules. As shown in Fig. 5B, a significant decrease in p-Jak2/JAK2 and p-STAT5/STAT5 ratios was observed in DLAT-silenced cells compared to normal cells, suggesting that the JAK2/STAT5 pathway was inactivated in the absence of DLAT. Treatment of DLAT-silenced cells with the JAK2/STAT5 activator, Butyzamide, restored p-JAK2/JAK2 and p-STAT5/STAT5 ratios, as well as SREBP1 levels (Fig. 5C). Similarly, reductions in triglyceride content (Fig. 5D), cholesterol content (Fig. 5E) and neutral lipid content (Fig. 5F) associated with knockdown of DLAT were restored following treatment with Butyzamide. Consistent with these findings, we examined p-STAT5 and STAT5 expression in paired human OC tissues and adjacent normal tissues. Western blot analysis revealed that the p-STAT5/STAT5 ratio was significantly higher in tumor tissues compared to adjacent normal tissues (Figure S1). Together, these findings demonstrate that DLAT upregulates SREBP1 expression and affects lipid metabolism through the JAK2/STAT5 signaling pathway.

Fig. 5
figure 5

DLAT upregulates SREBP1 expression and affects lipid metabolism through the JAK2/STAT5 signaling pathway in OC cells. (A) GSEA analysis of TCGA ovarian cancer dataset showing positive correlation between DLAT expression and the JAK-STAT signaling pathway. (B) Western blot analysis was used to examine changes in key JAK2/STAT5 signaling molecules (p-JAK2, p-STAT5, JAK2 and STAT5) in DLAT-silenced SKOV3 or OVCAR3 cells. Non-transduced SKOV3 or OVCAR3 cells were used as the controls. (C-F) DLAT-silenced SKOV3 or OVCAR3 cells were treated with the JAK2/STAT5 activator Butyzamide (3 µM) for 24 h. (C) Western blot analysis of p-JAK2, p-STAT5, JAK2, STAT5 and SREBP1 expression levels. (D-E) Triglyceride (D) and cholesterol (E) contents were determined in the indicated cells. (F) Nile Red staining was used to assess cellular neutral lipids. Nuclei were stained with Hoechst (blue). Scale bar = 50 μm. Data are presented as the mean ± SD, n = 3. Statistical comparisons were made between sh-NC versus sh-DLAT groups, and between sh-DLAT + DMSO versus sh-DLAT + Butyzamide groups. ***P < 0.001 and **P < 0.01

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SREBP1 is essential for DLAT-mediated OC cell growth and metastasis in vitro

We next sought to determine whether the effects of DLAT on OC cell growth and metastasis were mediated through SREBP1. CCK-8 assay data revealed that the reduction in cell growth observed in DLAT-silenced cells was restored following overexpression of SREBP1 (Fig. 6A). EdU and colony formation data were consistent with these findings (Fig. 6B-C). Similarly, the reduction in migration, invasion and wound healing observed in the absence of DLAT, was rescued by SREBP1 overexpression (Fig. 6D-E). Together, these findings suggest that the effects of DLAT on cell growth and metastasis are mediated through SREBP1.

Fig. 6
figure 6

SREBP1 is critical for DLAT-mediated OC cell growth and metastasis in vitro. SKOV3 or OVCAR3 cells were divided into the following treatment groups: sh-NC, sh-DLAT, sh-DLAT + EV (empty vector), and sh-DLAT + oeSREBP1. (A) The CCK-8 assay was used to assess the proliferative ability of cells in the indicated treatment groups. (B) The EdU assay was used to determine the proliferative ability of the indicated cells. Scale bar = 50 μm. (C) The colony formation assay was used to examine the proliferative ability of the indicated cells. (D) Transwell migration and invasion assays were used to determine the migratory and invasive abilities of the indicated cells. Scale bar = 50 μm. (E) The wound-healing migration assay was used to determine the migratory ability of the indicated cells. Scale bar = 100 μm. Data are presented as the mean ± SD, n = 3. Statistical comparisons were made between sh-NC versus sh-DLAT groups, and between sh-DLAT + EV versus sh-DLAT + oeSREBP1 groups. ***P < 0.001, **P < 0.01, and *P < 0.05

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DLAT promotes OC cell growth and metastasis by regulating lipid metabolism through the modulation of SREBP1 in vivo

Finally, we examined the effects of DLAT on tumor growth in vivo using a subcutaneous tumor model in mice. As shown in Fig. 7A-C, tumors derived from sh-DLAT-treated SKOV3 and OVCAR3 cells were significantly smaller in terms of volume and weight than control tumors. Tumors derived from DLAT-silenced cells overexpressing SREBP1 were significantly larger than sh-DLAT-derived tumors. IHC analysis of tumor tissue sections revealed a significant reduction in SREBP1 and Ki-67 staining in sh-DLAT-derived tumors, which was reversed following overexpression of SREBP1 (Fig. 7D). Similarly, the reduction in neutral lipids (Fig. 7E), triglyceride content (Fig. 7F) and cholesterol content (Fig. 7G) observed in tumor tissue from sh-DLAT-treated cells was reversed following SREBP1 overexpression. Furthermore, Western blot analysis showed that DLAT knockdown significantly decreased the p-STAT5/STAT5 ratio in xenograft tumor tissues from both SKOV3 and OVCAR3 cells, while SREBP1 overexpression reversed this effect (Fig. 7H). Together, these results demonstrate that DLAT promotes OC cell growth and metastasis through the regulation of lipid metabolism via SREBP1 in vivo.

Fig. 7
figure 7

DLAT promotes OC cell growth and metastasis by regulating lipid metabolism through modulation of SREBP1 in vivo. In vivo subcutaneous tumor models were established by injecting mice with sh-NC-, sh-DLAT- or sh-DLAT + oeSREBP1-treated SKOV3 or OVCAR3 cells. (A-C) Representative images showing resected subcutaneous tumors from indicated SKOV3 or OVCAR3 cell-injected groups in nude mice (A), n = 6. Tumor growth rates and weights were measured (B, C). (D) IHC staining of DLAT, Ki-67 and SREBP1 in tumor tissue sections from the various treatment groups. Scale bar = 200 μm. (E) Oil red O staining was used to measure neutral lipids in tumor tissue sections from the various treatment groups. Scale bar = 200 μm, n = 5. (F) Triglyceride levels were measured in tumor tissue sections from the various treatment groups, n = 5. (G) Cholesterol levels were assessed in tumor tissue sections from the various treatment groups, n = 5. (H) Western blot analysis of p-STAT5 and STAT5 expression in xenograft tumor tissues derived from SKOV3 and OVCAR3 cells with indicated treatments (sh-NC, sh-DLAT, or sh-DLAT + oeSREBP1), n = 2. Data are presented as the mean ± SD. ***P < 0.001, **P < 0.01, and *P < 0.05

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Fig. 8
figure 8

DLAT promotes ovarian cancer progression via JAK2/STAT5/SREBP1-mediated lipid metabolism. Schematic diagram showing the mechanism of DLAT in promoting ovarian cancer progression. In ovarian cancer cells, DLAT activates JAK2/STAT5 signaling pathway, leading to STAT5 phosphorylation and nuclear translocation. Nuclear p-STAT5 promotes SREBP1 transcription. Subsequently, SREBP1 enhances the expression of lipid metabolism-related enzymes (including FASN, ACC, ACLY, and SCD). The activation of this pathway results in increased lipid synthesis, ultimately promoting ovarian cancer cell proliferation and metastasis. Conversely, DLAT silencing suppresses this signaling cascade, reduces cellular lipid content, and impairs tumor progression

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Discussion

Here, we identify a role for the PDC member DLAT in OC. We show that DLAT expression correlates with tumor stage and is associated with poor prognosis. DLAT expression leads to increased expression of SREBP1, a major regulator of lipid synthesis enzymes. Mechanistically, we find that the JAK2/STAT5 pathway is activated by DLAT overexpression, identifying a DLAT/JAK2/STAT5/SREBP1 pathway that is critical for OC proliferation in vitro and in vivo.

DLAT is a mitochondrial protein involved in glucose metabolism [37], acting as the E2 subunit of the PDC in the catabolic glucose pathway and linking glycolysis to the Krebs’ cycle [32]. Aberrant metabolism including glycolysis and lipid metabolism has been implicated in promoting tumor growth and metastasis [38], and upregulation of DLAT has been previously reported in different types of cancer [33, 34, 36]. Here, we show for the first time, that DLAT is upregulated in OC patient tumor tissue and OC cell lines and is associated with worse patient prognosis. Thus, DLAT could serve as a potential marker for prognosis in OC patients.

We found that DLAT knockdown impaired OC cell proliferation and migration/invasion in vitro, suggesting that DLAT was required for tumor growth and migration, consistent with previous reports in gastric cancer [33], HCC [34] and lung cancer [36]. In addition, we found that DLAT knockdown led to a reduction in cellular neutral lipid, triglyceride and cholesterol levels, as well as a reduction in the expression of lipogenesis-related enzymes, including FASN, ACLY, ACC1, and SCD1. The expression of these enzymes is controlled by one of the master regulators of lipid homeostasis, SREBP1 [39]. Here, we found that DLAT and SREBP1 were positively correlated in OC patient tissue samples. In addition, we demonstrated that knockdown of DLAT significantly reduced SREBP1 expression levels resulting in the reduced expression of FASN, ACC, ACLY and SCD, and lower fatty acid content. Overexpression of SREBP1 in DLAT-silenced cells restored FASN, ACC, ACLY and SCD expression levels and fatty cid levels, suggesting that DLAT regulates lipid metabolism in OC via upregulation of SREBP1. Upregulation of SREBP1 has been implicated in regulating lipogenesis in other types of cancer. For example, the PDC has been shown to control the expression of SREBP1 target genes to sustain lipogenesis in prostate cancer [40], while long chain acyl CoA synthetase 4 (ACSL4) has been shown to reprogram fatty acid metabolism in HCC through the c-Myc/SREBP1 pathway [41]. Although SREBP1 has previously been shown to be required for OC growth and progression [42, 43], our study is the first to describe a link between DLAT and SREBP1.

Mechanistically, we found that DLAT expression was associated with activation of the JAK2/STAT5 pathway in OC cells. Previous studies have shown that STAT5 promotes SREBP1 expression in HCC [44], providing a mechanistic link between DLAT, STAT5, SREBP1 and lipid homeostasis. Previous studies have also shown that STAT5 localizes to the mitochondria and interacts directly with DLAT, leading to inactivation of the PDC and promotion of the Warburg effect [45, 46]. Our results show for the first time that DLAT-induced SREBP1 is mediated via JAK2/STAT5 in OC cells.

Identification of a potential DLAT/JAK2/STAT5/SREBP1 signaling pathway that drives OC progression through the reprogramming of lipid metabolism would provide multiple avenues to explore as potential prognostic markers and therapeutic targets. Currently, several inhibitors of STAT5 have been developed and their therapeutic potential in OC is being examined in clinical trials [47,48,49], while some success has been reported in other types of cancer [50, 51]. For example, the antipsychotic drug and STAT5 inhibitor pimozide has been shown to decrease the survival of chronic myelogenous leukemia cells resistant to kinase inhibitors [52], while small molecule STAT5-SH2 domain inhibitors reportedly exhibit potent antileukemia activity [53]. The potential role of JAK inhibitors in the treatment of OC has also been recently reviewed [54], while a phase I and randomized phase II clinical trial using the JAK inhibitor ruxolitinib with frontline neoadjuvant therapy for the treatment of advanced OC patients has been reported [55]. Our results showing a role for JAK2/STAT5 in OC cell lipogenesis suggests that inhibiting the JAK2/STAT5 pathway in OC may be a novel therapeutic strategy.

Finally, the recently reported association between DLAT and a novel form of copper-dependent cell death called cuproptosis [56,57,58] might also be worth exploring as a potential therapeutic target. Lipoylated DLAT forms aggregates in the presence of copper, which results in cell death due to loss of function of the PDC [56]. FDX1 was recently shown to inhibit thyroid cancer malignancy by promoting cuproptosis through regulation of DLAT lipoylation [59]. However, it remains unclear whether treatment of OC cells (or other cancer cells that overexpress DLAT) with copper ionophore would result in cell death. Future studies are required to directly test this possibility.

While our findings highlight the importance of the DLAT/JAK2/STAT5/SREBP1 pathway in OC progression, it is crucial to recognize that tumors are complex adaptive systems that can develop alternative pathways to maintain their growth and survival [60, 61]. Cancer cells demonstrate remarkable metabolic flexibility and can adapt to various therapeutic interventions by activating compensatory mechanisms. This adaptability suggests that targeting a single enzyme or pathway may not be sufficient as a therapeutic strategy. Instead, a multi-target approach that simultaneously addresses multiple metabolic vulnerabilities might be more effective in treating OC. This could involve combining DLAT pathway inhibition with other metabolic interventions or conventional therapies to prevent the development of resistance mechanisms and improve treatment outcomes.

Conclusion

In summary, the current study has identified a novel DLAT/JAK2/STAT5/SREBP1 axis that reprograms lipid metabolism in OC and provides insights into the development of potential therapeutic approaches to target this pathway in the treatment of OC (Fig. 8).

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the Public Welfare Project “JiShiQiYi” of Beijing Health Alliance Charitable Foundation (Grant No.KM-JSQY-002), and the “ZaiDing-Le” Foundation from Beijing Kanghua Foundation for the Development of Traditional Chinese and Western Medicine (Grant No. KH-2020- LJJ-008).

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  1. Hui Wang, Shen Luo and Yue Yin contributed equally to this work.

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  1. Department of Gynecology, Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China

    Hui Wang, Shen Luo, Yue Yin, Yang Liu, Xiaomei Sun, Ling Qiu & Xin Wu

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Contributions

Hui Wang, Shen Luo, and Yue Yin: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data Curation, Writing - Original Draft, Visualization, Writing - Review & Editing; Yang Liu: Software, Formal analysis, Data Curation, Visualization; Xiaomei Sun: Investigation, Resources, Data Curation; Ling Qiu: Conceptualization, Validation, Resources, Writing-Review & Editing, Supervision; Xin Wu: Conceptualization, Methodology, Validation, Resources, Writing - Review & Editing, Supervision, Project administration, Funding acquisition.

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Correspondence to Ling Qiu or Xin Wu.

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This study was approved by the Ethics Committee of Obstetrics & Gynecology Hospital of Fudan University. All patients provided written informed consent prior to participation in the study. The study was conducted in accordance with the Declaration of Helsinki and followed the relevant institutional and national guidelines. All animal experiments were performed following protocols approved by the Institutional Animal Care and Use Committee of Obstetrics & Gynecology Hospital of Fudan University.

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Wang, H., Luo, S., Yin, Y. et al. DLAT is involved in ovarian cancer progression by modulating lipid metabolism through the JAK2/STAT5A/SREBP1 signaling pathway. Cancer Cell Int 25, 25 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12935-025-03656-7

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Cancer Cell International

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