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. 2026 Apr 1;42(1):63. doi: 10.1007/s10565-026-10173-4

ALKBH5/IGF2BP1-mediated m6A demethylation of TRIM37 promotes pancreatic cancer tumorigenesis and glycolysis by mediating RBMX degradation

Cheng Yan 1,#, Xuan Li 2,#, Ying Zhao 4,#, Jinhui Chen 2, Xinke Peng 5, Daichao Wu 1,✉, Yabin Chang 3,✉, Guodong Chen 1,✉
PMCID: PMC13167913  PMID: 41922631

Abstract

Background

The upregulation of the ubiquitin ligase TRIM37 is associated with an adverse prognosis in pancreatic ductal adenocarcinoma (PDAC). This study investigates the mechanism and oncogenic consequence of TRIM37 upregulation in PDAC development.

Methods

TRIM37 expression was assessed by qPCR and Western blotting. The effects of TRIM37 knockdown and overexpression on cell proliferation, colony formation, stemness capacity was investigated through in vitro assays, and the role in PDAC was evaluated through vivo experiments. RNA immunoprecipitation assay and Actinomycin D assay were performed to detect the mechanism of TRIM37 upregulation. The TRIM37 and RBMX interaction were determined through co-immunoprecipitation and immunofluorescence.

Results

We identified TRIM37 as a critical oncoprotein in PDAC, and its overexpression was strongly correlated with poor prognosis. As a ubiquitin ligase, TRIM37 targets the tumor suppressor RBMX for proteasomal degradation, promoting glycolytic reprogramming and driving aggressive cancer phenotypes, including enhanced proliferation, migration, and stemness. Furthermore, we found that the ALKBH5-IGF2BP1 axis promotes TRIM37 expression by controlling N6-methyladenosine (m6A) modification of TRIM37 mRNA and enhancing its transcript stability.

Conclusions

Our findings establish the ALKBH5/IGF2BP1-TRIM37-RBMX signaling axis as a pivotal driver of PDAC progression, highlighting the intersection of m6A modification, ubiquitin signaling, and metabolic reprogramming. These findings may provide potential therapeutic avenues for this intractable malignancy.

Supplementary information

The online version contains supplementary material available at 10.1007/s10565-026-10173-4.

Keywords: Pancreatic ductal adenocarcinoma, N6-methyladenosine, TRIM37, RBMX, Ubiquitination, Glycolysis

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal malignancy with difficulty in early detection limiting therapeutic options and resulting in a dismal prognosis (McGuigan et al. 2018; Chen et al. 2025; Siegel et al. 2025). Tripartite motif-containing protein 37 (TRIM37) is a RING-type E3 ubiquitin ligase located at 17q23 (Wang et al. 2017), which functions as an oncogenic H2A ubiquitin ligase. Its amplification and overexpression drive tumorigenic programs (Bhatnagar et al. 2014). Emerging evidence has indicated that TRIM37 may function as an oncogene across multiple cancer types, including breast cancer (Bhatnagar et al. 2014), endometrial cancer (Zhou et al. 2024) and renal cell carcinoma (Miao et al. 2021). While recent studies have associated TRIM37 with chemoresistance in PDAC (Chen et al. 2020; Do et al. 2022), its specific role in the initiation and progression of this malignancy has not yet been elucidated.

Cancer entails profound metabolic rewiring typified by the Warburg effect—preferential aerobic glycolysis despite adequate oxygen (Vander Heiden et al. 2009; Li et al. 2024). In PDAC, a desmoplastic, hypoxic and nutrient-poor microenvironment entrenches this glycolytic program (Koong et al. 2000; Hosein et al. 2020; Masugi 2022). Oncogenic KRAS and HIF-1α upregulate glucose transporters and glycolytic enzymes while dampening oxidative phosphorylation, and loss of p53 further accelerates glycolysis via TIGAR-mediated control of fructose-2,6-bisphosphate levels (Chen et al. 2001; Bensaad et al. 2006; Semenza 2011; Ying et al. 2012; Bailey et al. 2016). In addition to ATP production, elevated glycolysis supplies biosynthetic precursors via the pentose phosphate and serine–glycine pathways to sustain rapid biomass production (Lunt and Vander Heiden 2011; Locasale 2013; Patra and Hay 2014). Nevertheless, the regulatory nodes that fine-tune PDAC glycolysis—and may be therapeutically tractable—remain incompletely defined.

In this study, we provide evidence that TRIM37 is a critical oncoprotein that is aberrantly overexpressed at the protein and mRNA levels in PDAC and is correlated with poor patient prognosis. Elevated TRIM37 expression is positively correlated with tumor size, TNM stage and tumor metastasis. Functional experiments demonstrated that TRIM37 drives PDAC progression by enhancing malignant behaviors, including cell proliferation, migration, invasion, and stemness in vitro, as well as promoting tumor growth and metastasis in vivo. Mechanistically, TRIM37 functions as an E3 ubiquitin ligase to induce ubiquitin-dependent degradation of RNA binding motif protein X-linked (RBMX), thereby enhancing glycolysis and facilitating tumor progression. Additionally, we elucidated the upstream regulatory mechanism, revealing that the downregulation of the m6A demethylase ALKBH5 increases m6A levels on TRIM37 mRNA. This hypermethylated transcript is then recognized by the m6A reader IGF2BP1, which enhances its stability and drives aberrant TRIM37 overexpression. Our findings establish the ALKBH5-IGF2BP1/TRIM37/RBMX axis as a crucial regulatory pathway in PDAC, highlighting TRIM37 as a promising therapeutic target.

Methods

Ethics statement and subjects

A total of 50 PDAC patients who underwent surgery at the Second Xiangya Hospital during 2022–2025 were included in this study. The Clinicopathological data, including age, gender, smoking status, CA199, tumor size, TNM stage, and metastasis, were collected. The study was approved by the Ethics Committee of the Second Xiangya Hospital. All the samples were collected with the informed consent of these patients.

Chemicals and antibodies

TRIzol reagent and Lipofectamine 3000 transfection reagent were purchased from Invitrogen. Short hairpin RNA-TRIM37 (shTRIM37), small interfering RNA-RBMX (siRBMX), small interfering RNA-ALKBH5 (siALKBH5), pcDNA3.1 vectors expressing TRIM37, RBMX or ALKBH5, and their corresponding control vectors were purchased from GenePharma. CD133 (cat# 64,326), SOX2 (cat# 23,064), OCT4 (cat# 2750), GLUT1 (cat#12,939), HK2 (cat#2867), LDHA (cat#2012), PKM2 (cat#4053), RBMX (cat#14,794), ALKBH5 (cat#80,283) and β-actin (cat#4967) antibodies were purchased from Cell Signaling Technology; TRIM37 (cat#ab264190), IGF2BP1 (cat#ab184305) and Ki67 (cat# ab15580) antibodies were purchased from Abcam.

Cell culture and cell transfection

All cell lines were maintained containing 10% fetal bovine serum and 1% penicillin–streptomycin, and incubated at 37℃ under humidified air with 5% CO2. Regular mycoplasma testing was performed to ensure that all the cultures were free from contamination. Cellular transfections were carried out via Lipofectamine 3000 in accordance with the manufacturer’s protocol.

Cell counting kit-8 assay

1 × 103 cells per well were initially seeded in 96-well plates, and cultured at 37 °C for up to 4 days. 10 μL of CCK-8 reagent was supplemented to each well, followed by another 2-h incubation at 37℃. The absorbance at 450 nm was subsequently measured with a microplate reader to assess cell proliferation.

Colony formation assay

The colony formation assay was performed by seeding 1,000 cells into each well of a 6-well plate, followed by an incubation period of 8–14 days. Subsequently, the cells were immobilized with 70% ethanol and dyed with 0.5% crystal violet for 15 min. Colonies with over 50 cells were considered positive and were counted to determine the clonogenic survival rate.

Cell migration and invasion assays

Cell motility was examined using a Transwell system. Inserts were coated with Matrigel for invasion experiments or left uncoated for migration experiments. Following seeding in the upper chamber, cells were exposed to serum-containing medium in the lower chamber. At 24 h post-incubation, cells that did not migrate were gently removed, whereas cells on the underside of the membrane were fixed, crystal violet-stained, and photographed. The number of stained cells was then quantified to determine the migration/invasion rate.

Quantitative reverse‑transcriptase PCR (qrt-PCR)

TRIzol reagent was utilized in accordance with the instructions provided by the supplier for total RNA extraction from the indicated cells and tissue samples. RNA quality and purity were assessed through agarose gel electrophoresis. cDNA synthesis was carried out using ImPro-II reverse transcriptase along with reverse-transcription primers. Fast Start Universal SYBR Green Master Mix was employed for qRT-PCR assays. Details of primer sequences employed in this work are provided in Table S1.

Western blotting analysis

Total protein was isolated from homogenized tissue or cultured cells using lysis buffer. The bicinchoninic acid assay was utilized to standardize protein concentrations. We separated 25 µg of protein per sample by SDS‒PAGE and transferred the resolved proteins onto PVDF membranes. The membranes were incubated with primary antibody followed by secondary antibody in sequence. Protein bands were detected via ECL.

Co-immunoprecipitation (Co-IP)

Co-IP experiments were performed using pancreatic cancer cell lysates. Cell lysis was performed in inhibitor-supplemented NP40 lysis buffer (ice, 30 min), and supernatants were collected post centrifugation (12,000 × g, 10 min, 4 °C). Supernatants were immunoprecipitated with 5 µg antibodies/isotype controls (4 °C, 2 h), then incubated with 100 µL A/G agarose beads overnight at 4 °C with rotation. Beads were washed thrice, and bound complexes were eluted in 2 × SDS sample buffer (100 °C, 10 min). Finally, Western blotting analysis was performed to detect the target protein and its interacting proteins.

Immunohistochemistry (IHC)

The tissue samples were fixed in 10% formalin for a minimum of 48 h and embedded in paraffin following established protocols. Sections were incubated with primary antibodies overnight at 4℃ and subsequently processed using the UltraVision Quanto Detection System HRP DAB Ki in accordance with the manufacturer’s instructions. The expression levels were assessed by examining 10 randomly selected high-magnification fields at 200 × via an Olympus CX23 microscope.

Immunofluorescence staining

Cells were seeded in 12-well plates and cultured to 50% confluency. Subsequent steps included fixation with 4% paraformaldehyde (10 min) and permeabilization with 0.1% Triton X-100 (10 min). Following a 30-min blocking step with 5% BSA, the cells were probed with primary antibodies against TRIM37 and RBMX at 4 °C overnight. Following washes, cells were treated with fluorochrome-tagged secondary antibodies for 1 h, and DAPI was used to stain nuclei for 5 min. Finally, images were captured under a fluorescence microscope to visualize the fluorescence signals.

RNA immunoprecipitation (RIP) assay

RIP assay was performed with the Magna RIP™ RNA-Binding Protein Immunoprecipitation Kit. Briefly, the cell lysates were incubated with antibody-conjugated Sepharose beads at 4 °C for 6 h. The immunocomplexes were then treated with 0.1% SDS and Proteinase K at 55 °C for 30 min to digest the proteins. Co-precipitated RNAs and proteins were analyzed by quantitative RT-PCR and Western blotting, respectively.

Establishment of subcutaneous tumor and lung metastasis models

All animal-related procedures were authorized by the Animal Care Committee of the Second Xiangya Hospital (NO. 20,251,279). 6 weeks old-Male BALB/c nude mice were obtained from the Shanghai Laboratory Animal Center. A total of 1 × 106 ASPC-1 cells stably expressing TRIM37 via lentiviral knockdown or carrying empty vectors were injected subcutaneously into the hypochondria of the mice (n = 5 per group). Tumor growth was monitored over a period of 4 weeks, after which the tumors were excised, and their weight and volume were measured.

To establish a lung metastasis model, 1 ✕ 106 ASPC-1 cells with TRIM37 knockdown (shTRIM37) or the control vector were resuspended in 100 µL of PBS. Nude mice (n = 5 per group) received tail vein injections of the cell suspension under sterile conditions. All the mice were monitored for tumor growth, and their lung tissues were harvested at 4 weeks post-injection for analysis. The tumor burden was assessed by HE staining.

Statistical analysis

Data are presented as mean ± standard deviation (SD) from at least three independent experiments. Statistical analyses and graphing were performed using GraphPad Prism 10. Group differences were compared using Student’s t-test or ANOVA. Pearson correlation was applied to examine associations between gene expression levels. Statistical significance was defined as a p-value < 0.05.

Results

Elevated trim37 expression in PDAC is correlated with poor prognosis

We firstly investigated the involvement of TRIM37 in PDAC by evaluating its mRNA expression in The Cancer Genome Atlas (TCGA) datasets and our own cohort. The results showed that TRIM37 mRNA was significantly upregulated in both TCGA datasets (Fig. 1A) and our cohort (Fig. 1B) compared with adjacent normal tissues. Furthermore, Western blotting analysis revealed that TRIM37 protein levels were elevated in PDAC tissues relative to matched normal samples (Fig. 1C). In terms of clinical and pathological characteristics, we found that abnormal expression of TRIM37 was closely associated with TNM stage, tumor size, and distant metastasis (Table S2). Additionally, analysis of the GEPIA database (http://cancer-pku.cn) and Kaplan–Meier plotter (https://kmplot.com/analysis/) indicated that high TRIM37 expression was negatively correlated with both overall survival (OS) and disease-free survival (DFS) in PDAC patients (Fig. 1D–G). Collectively, these findings highlight that TRIM37 overexpression is a key driver of PDAC progression and serves as a potential prognostic marker for poor clinical outcomes.

Fig. 1.

Fig. 1

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TRIM37 is overexpressed in PDAC and is correlated with poor prognosis. (A) TRIM37 mRNA expression levels in PDAC tumor tissues (n = 179) compared with adjacent normal tissues (n = 171) from the TCGA dataset. (B) qRT-PCR analysis of TRIM37 mRNA expression levels in PDAC tumor tissues (n = 50) and adjacent normal tissues (n = 50). (C) Western blotting analysis of TRIM37 protein expression in eight paired tumor and adjacent normal tissues. (D, E) Kaplan-Meierr survival curves showing the correlation between high TRIM37 expression and overall survival in PDAC patients from the TCGA database. (F, G) Kaplan–Meier survival curves showing the correlation between high TRIM37 expression and disease-free survival in PDAC patients from the TCGA database. The data are presented as the means ± SD. *P < 0.05, **P < 0.01

Trim37 knockdown inhibits cell growth, migration and stemness in PDAC cell lines

To assess the functional significance of TRIM37 in PDAC, we first profiled its basal expression across PDAC cell lines and found the highest levels in ASPC-1 and PANC-1 cells (Figure S1A, B). Based on these patterns, we generated ASPC-1 and PANC-1 cells with stable TRIM37 knockdown, which was validated by qPCR and Western blotting (Figure S1C, D). Both CCK-8 and colony formation assay results showed consistently that silencing TRIM37 exerted a significant inhibitory effect on PDAC cell growth (Fig. 2A-C). Moreover, TRIM37 depletion resulted in a marked reduction in migration and invasion of both ASPC-1 and PANC-1 cells compared with control cells (Fig. 2D, E). CD133, SOX2, and OCT4 are widely recognized as key stemness markers, with CD133 being used to identify cancer stem cells(Moreno-Londoño and Robles-Flores 2024), whereas SOX2 and OCT4 are crucial transcription factors that regulate self-renewal and pluripotency in stem cells(Hou, Nie et al. 2025). We found that silencing TRIM37 markedly reduced the protein and mRNA levels of CD133, OCT4 and SOX2 in both cell lines (Fig. 2F, G). These results show that TRIM37 knockdown inhibits malignant behaviors, including increased proliferation, migration, invasion, and stemness, in PDAC cell lines.

Fig. 2.

Fig. 2

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TRIM37 knockdown suppresses malignant phenotypes in PDAC cells. (A) Cell proliferation curves of ASPC-1 and PANC-1 cells with TRIM37 knockdown versus control cells, measured by CCK-8 assays. (B, C) Cell proliferation ability of ASPC-1 and PANC-1 cells with TRIM37 knockdown versus control cells, measured by colony formation assays. (D, E) Migration and invasion abilities of ASPC-1 and PANC-1 cells with TRIM37 knockdown versus control cells, measured by Transwell assays. (F, G) The stemness abilities of ASPC-1 and PANC-1 cells with TRIM37 knockdown versus control cells were measured by analyzing the expression of the stemness markers CD133, OCT4, and SOX2. (F) Western blotting images of CD133, OCT4, and SOX2 protein levels. (G) The mRNA expression levels of CD133, OCT4, and SOX2 were determined by qRT-PCR analysis. The data are presented as means ± SD (n = 3). **P < 0.01

Trim37 promotes cell growth, migration and stemness in PDAC cell lines

Next, two pancreatic cancer cell lines, MIA PaCa-2 and BxPC-3, which exhibit low endogenous TRIM37 expression, were selected to generate TRIM37-overexpressing derivatives. The successful transfection and overexpression of TRIM37 were confirmed via Western blotting and qPCR (Figure S1C, D). TRIM37 overexpression significantly enhanced cell proliferation, as evidenced by cell growth curves and colony formation assays (Fig. 3A-C). Additionally, TRIM37 overexpression promoted migration, invasion (Fig. 3D, E), and stemness (Fig. 3F, G) in both MIA PaCa-2 and BxPC-3 cells, as demonstrated by transwell assays, and increased the expression of stemness markers. These findings collectively suggest that TRIM37 overexpression promotes a range of malignant behaviors in PDAC cell lines.

Fig. 3.

Fig. 3

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TRIM37 overexpression promotes malignant phenotypes in PDAC cells. (A) Cell proliferation curves of MIA PaCa-2 and BxPC-3 cells transfected with TRIM37 overexpression or vector control, measured by CCK-8 assay. (B, C) Cell proliferation ability of MIA PaCa-2 and BxPC-3 cells with TRIM37 overexpression versus control cells, measured by colony formation assays. (D, E) Migration and invasion abilities of MIA PaCa-2 and BxPC-3 cells with TRIM37 overexpression versus control cells, measured by Transwell assays. (F, G) The stemness abilities of MIA PaCa-2 and BxPC-3 cells with TRIM37 overexpression versus control cells were measured by analyzing the expression of the stemness markers CD133, OCT4, and SOX2. (F) Western blotting images of CD133, OCT4, and SOX2 protein levels. (G) The mRNA expression levels of CD133, OCT4, and SOX2 were determined by qRT-PCR analysis. The data are presented as means ± SD (n = 3). **P < 0.01

TRIM37 knockdown inhibits tumor growth and metastasis in vivo

We next assessed the in vivo role of TRIM37 in PDAC. PDAC cells stably transduced with either the control vector or shTRIM37 were implanted subcutaneously into nude mice. Compared with the control, TRIM37 knockdown significantly impaired xenograft growth, as evidenced by smaller tumor volumes and lower tumor weights at four weeks (Fig. 4A–C). Additionally, Ki-67 is a well-established marker of cell proliferation, and its expression is correlated with the proliferative activity of tissues and tumors (Chirieac 2016). Ki-67 immunostaining revealed a significant reduction in proliferating cells in the shTRIM37 tumors, further confirming the impaired growth (Fig. 4D). We subsequently evaluated the effects of TRIM37 on distant metastasis by injecting PDAC cells through the tail vein and observed that TRIM37-knockdown could inhibit lung implantation of PDAC cells (Fig. 4E). Collectively, these data demonstrate that TRIM37 promotes PDAC tumor growth and metastasis in vivo.

Fig. 4.

Fig. 4

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TRIM37 knockdown inhibits tumor growth and metastasis in vivo. (A) Schematic illustration of the subcutaneous xenograft tumor model in nude mice (n = 5). (B, C) Subcutaneous tumors derived from ASPC-1 cells with TRIM37 knockdown versus control cells, analyzed for (B) tumor volume and (C) weight. (D) Representative IHC staining images of Ki-67 proliferation index in shCtrl and shTRIM37 xenograft tumor tissues (n = 5). (E) Representative lung and HE staining images of shCtrl and shTRIM37 xenograft tumor tissues (n = 5 mice). The data are presented as means ± SD. **P < 0.01

Trim37 enhances glycolysis in PDAC cell lines

To elucidate the mechanisms by which TRIM37 influences the progression of PDAC, we conducted RNA-Seq analysis on PDAC cells with TRIM37 knockdown, comparing them with control vector-transduced cells. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed significant alterations in glycolysis in response to TRIM37 deficiency in ASPC-1 cells (Fig. 5A, B). To investigate the potential link between TRIM37 expression and glycolytic metabolism, we examined the expression levels of key glycolysis-related genes following TRIM37 knockdown. Our results demonstrated that TRIM37 knockdown led to the downregulation of glycolysis-related genes, including Glucose Transporter1 (GLUT1), hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and pyruvate kinase M2 (PKM2) (Fig. 5C). Consistent with these gene expression changes, we observed a significant reduction in glucose consumption, ATP production, and lactate production in the TRIM37-deficient cells (Fig. 5D-F). In addition, we performed immunohistochemical staining on subcutaneous xenograft tumors to assess the expression of glycolysis-related enzymes. Compared with the control group, TRIM37 knockdown markedly reduced the expression levels of GLUT1, HK2, and LDHA (Figure S2A). These findings support the hypothesis that TRIM37 acts as a positive regulator of glycolysis in PDAC. Furthermore, 2-deoxy-D-glucose (2-DG), a glucose analog, suppresses glycolysis by inhibiting hexokinase, disrupting glucose metabolism and inducing energy stress, which ultimately inhibits cancer cell growth (Zhang et al. 2014). Pharmacologic inhibition of glycolysis using 2-DG in TRIM37-overexpressing MIA PaCa-2 cells markedly suppressed PDAC cell viability, migration and invasion, as demonstrated by colony formation assays (Fig. 5G) and transwell assays (Fig. 5H). Taken together, these findings suggest that TRIM37 enhances glycolytic metabolism, thereby promoting the progression of PDAC.

Fig. 5.

Fig. 5

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TRIM37 enhances glycolytic metabolism to promote PDAC progression. (A) Heatmap of the differential expression of TRIM37 knockdown versus control in ASPC-1 cells. (B) KEGG pathway enrichment analysis of the enriched pathways after TRIM37 silencing. (C) The protein expression levels of key glycolysis-related genes (GLUT1, HK2, LDHA, PKM2) in ASPC-1 and PANC-1 cells, with or without TRIM37 knockdown, were determined by Western blotting. (D-F) Functional assessments of glycolytic activity, glucose consumption (D), intracellular ATP production (E), and lactate production (F) were performed in ASPC-1 and PANC-1 cells, with or without TRIM37 knockdown. (G, H) Rescue experiments using the glycolytic inhibitor 2-Deoxy-D-glucose (2-DG). Colony formation (G) and Transwell invasion assays (H) were performed in MIA PaCa-2 cells overexpressing TRIM37 treated with or without 2-DG. The data are presented as means ± SD (n = 3). **P < 0.01

TRIM37 destabilizes RBMX via ubiquitin proteasome pathway

To identify proteins interacting with TRIM37, we performed mass spectrometry and identified RBMX as a potential TRIM37-binding partner. A study had identified RBMX as a tumor suppressor in pancreatic cancer (Alors-Pérez et al. 2024), with lower RBMX levels being associated with patients survival (Figure S2B). Co-IP assays were subsequently performed in ASPC-1 and PANC-1 cells to verify the interaction between TRIM37 and RBMX. The results revealed a physical interaction between TRIM37 and RBMX (Fig. 6A). Additionally, immunofluorescence staining demonstrated significant colocalization of TRIM37 and RBMX in both cell lines (Fig. 6B). To further elucidate the regulatory relationship between TRIM37 and RBMX, we conducted qRT-PCR and Western blotting. The results showed that RBMX acts downstream of TRIM37. Notably, the modulation of TRIM37 expression significantly altered RBMX protein levels, whereas neither TRIM37 knockdown nor overexpression affected RBMX mRNA expression (Fig. 6C, S2C), suggesting a post-transcriptional regulatory mechanism.

Fig. 6.

Fig. 6

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TRIM37 targets RBMX for ubiquitin-mediated degradation. (A) Immunoprecipitation assays showing the interaction between endogenous TRIM37 and RBMX in ASPC-1 and PANC-1 cells. (B) Immunofluorescence staining showing the subcellular localization and colocalization of TRIM37 (green) and RBMX (red) in ASPC-1 and PANC-1 cells. Nuclei are counterstained with DAPI (blue). Scale bars, 50 μm. (C) Effect of TRIM37 modulation on RBMX expression. RBMX protein levels upon TRIM37 knockdown (left) or overexpression (right). (D) Protein stability assay showing that the control and TRIM37-overexpressing MIA PaCa-2 and BxPC-3 cells were treated with cycloheximide (CHX) for the indicated times. RBMX protein levels were analyzed by Western blotting. (E) Western blotting of the effect of TRIM37 overexpression on the ubiquitination of MIA PaCa-2 cells. (F) Immunoprecipitation assays demonstrated the effects of TRIM37 overexpression on the ubiquitination of MIA PaCa-2 cells. (G) Examination of the influence of TRIM37 on specific ubiquitination types of RBMX. HEK293T cells were transfected with myc-RBMX and Flag-TRIM37 along with indicated HA-Ubiquitin mutants. Following MG132 treatment, cell extracts were immunoprecipitated by myc antibody and immunoblotted with HA antibody. The data are presented as means ± SD (n = 3). **P < 0.01

To examine whether TRIM37 influences the stability of RBMX, we performed protein half-life experiments. The results demonstrated that TRIM37 overexpression markedly reduced the stability of RBMX (Fig. 6D). Given that TRIM37 is an E3 ubiquitin ligase, we hypothesized that it promotes the ubiquitin-mediated degradation of RBMX. To test this hypothesis, we conducted ubiquitination assays. The results showed that TRIM37 overexpression promoted ubiquitin-mediated degradation of RBMX (Fig. 6E, F), indicating that TRIM37 regulates RBMX stability via the ubiquitin–proteasome pathway. Given that K48-linked ubiquitination is the canonical signal for 26S proteasome-mediated degradation (Grice and Nathan 2016), while K27/K29/K63 linkages have been linked to non-proteolytic signaling pathways (Wu et al. 2019; Yu et al. 2021; Zhu et al. 2021), we selected K27/K29/K48/K63 for linkage-specific validation. To achieve this, we co-transfected RBMX with a panel of HA-tagged ubiquitin mutants, each retaining only one of the four lysine residues (K27, K29, K48, or K63). Co-immunoprecipitation assays showed that TRIM37 markedly increased K48-linked polyubiquitin chains on RBMX, while moderately enhancing K27-linked polyubiquitination (Fig. 6G). This finding provides insight into the regulation of RBMX at the protein level without accompanying changes in its mRNA expression.

To explore the functional interplay between TRIM37 and RBMX, we generated double-knockdown and double-overexpressing cell models. In ASPC-1 cells, RBMX knockdown in the TRIM37-deficient background restored the expression levels of key glycolytic enzymes (Fig. 7A and B) as well as key glycolytic processes, including glucose consumption, ATP production, and lactate release (Fig. 7C-E). Conversely, in MIA PaCa-2 cells, co-overexpression of RBMX attenuated the TRIM37-driven enhancement of glycolysis (Fig. 7F-J). These metabolic changes were reflected in cellular behavior, and RBMX loss rescued the suppression of cell proliferation, migration, invasion and stemness caused by TRIM37 knockdown in ASPC-1 cells (Fig. 7K, S3A and S3C), whereas RBMX co-overexpression of oncogenic phenotypes promoted by TRIM37 in MIA PaCa-2 cells (Fig. 7L, S3B and S3D). Collectively, these results indicate that TRIM37 regulates glycolytic reprogramming and drives malignant phenotypes in PDAC cells by suppressing RBMX.

Fig. 7.

Fig. 7

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RBMX is a functional downstream effector of TRIM37. (A, B) Effects of RBMX knockdown in ASPC-1-shTRIM37 cells on glycolysis-related gene expression, (A) The mRNA expression levels of GLUT1, HK2 and LDHA were determined by qRT-PCR analysis. (B) Western blot images of GLUT1, HK2 and LDHA protein levels. (C-E) Effects of RBMX knockdown in ASPC-1-shTRIM37 cells on glycolytic metabolism, including ATP production (C), glucose consumption (D) and lactate production (E). (F, G) Effects of RBMX overexpression in MIA PaCa-2-TRIM37 cells on glycolysis-related gene expression, (F) The mRNA expression levels of GLUT1, HK2 and LDHA were determined by qRT-PCR analysis. (G) Western blotting images of GLUT1, HK2 and LDHA protein levels. (H-J) Effects of RBMX overexpression in MIA PaCa-2-TRIM37 cells on glycolytic metabolism, including ATP production (H), glucose consumption(I) and lactate production (J). (K) Effects of RBMX knockdown in ASPC-1-shTRIM37 cells on stemness ability, as measured by analyzing the expression of the stemness markers CD133, OCT4, and SOX2. (L) Effects of RBMX overexpression in MIA PaCa-2-TRIM37 cells on stemness ability, as measured by analyzing the expression of the stemness markers CD133, OCT4, and SOX2. The data are presented as means ± SD (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001

ALKBH5/IGF2BP1‑mediated m6A demethylation is involved in TRIM37 upregulation

ALKBH5, an RNA N6-methyladenosine (m6A) demethylase, plays a crucial role in modulating mRNA stability (Huang et al. 2021; Lai et al. 2022). To elucidate its role in PDAC, we first assessed ALKBH5 expression and found that PDAC tissues exhibited significantly reduced ALKBH5 mRNA levels compared with adjacent normal tissues (Fig. 8A). Notably, across pancreatic cancer specimens, we observed an inverse correlation between TRIM37 expression and ALKBH5 expression (Fig. 1C, 8B and 8D). To assess clinical significance, we performed survival analyses stratified by ALKBH5 expression. Our results demonstrated that there exists a positive correlation between high ALKBH5 expression and a favorable prognosis among PDAC patients (Fig. 8C). Knockdown of ALKBH5 increased TRIM37 protein abundance (Fig. 8E), while overexpression of ALKBH5 led to a reduction in TRIM37 levels (Fig. 8F). In parallel, ALKBH5 depletion elevated TRIM37 mRNA levels (Fig. 8G), whereas ALKBH5 overexpression decreased its transcript level (Fig. 8H). Furthermore, m6A-RIP (MeRIP) assays demonstrated that silencing ALKBH5 enhanced m6A modification of TRIM37 transcripts (Fig. 8I), while ALKBH5 overexpression decreased m6A methylation on TRIM37 mRNA (Fig. 8J). In actinomycin-D chase experiments, ALKBH5 depletion prolonged the mRNA half-life of TRIM37, whereas overexpression of ALKBH5 accelerated its degradation (Fig. 8K). Using luciferase reporters harboring either the wild-type TRIM37 sequence or an m6A-motif mutant, we found that ALKBH5 knockdown selectively boosted luciferase output from the wild-type reporter. In contrast, mutation of the candidate m6A site abolished this response, implicating m6A-dependent regulation in the maintenance of TRIM37 mRNA stability (Fig. 8L). m6A-dependent pathways involving IGF2BP1 have been implicated in PDAC therapy-response phenotypes, providing precedent for an m6A–IGF2BP1 mechanism in this context (Zhu et al. 2024; Cui et al. 2025). In MIA PaCa-2 cells, IGF2BP1 overexpression markedly increased TRIM37 protein and mRNA expression (Fig. 8M and N). In actinomycin D chase assays, IGF2BP1 overexpression prolonged the half-life of TRIM37 mRNA, indicating enhanced transcript stability (Fig. 8O). Collectively, these data indicate that the loss of ALKBH5 leads to increased m6A methylation of TRIM37 mRNA, which is mediated by IGF2BP1 to stabilize the transcript and promotes its expression in PDAC cells (Fig. 9).

Fig. 8.

Fig. 8

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ALKBH5 negatively regulates TRIM37 expression through m6A-dependent mRNA stability. (A) ALKBH5 mRNA expression levels in PDAC tissues compared with adjacent normal tissues from our patient cohort, as determined by qRT-PCR. (B) Western blotting of ALKBH5 protein expression in eight paired tumor and adjacent normal tissues. (C) Kaplan-Meierr survival curves showing the correlation between high ALKBH5 expression and OS in PDAC patients. (D) Correlation analysis between ALKBH5 and TRIM37 mRNA expression levels in pancreatic cancer specimens. (E) Effects of ALKBH5 knockdown in MIA PaCa-2 cells on TRIM37 protein level. (F) Effects of ALKBH5 overexpression in ASPC-1 cells on TRIM37 protein level. (G) Effects of ALKBH5 knockdown in MIA PaCa-2 cells on TRIM37 mRNA level. (H) Effects of ALKBH5 overexpression in ASPC-1 cells on TRIM37 mRNA level. (I) MeRIP assays followed by qPCR showing the enrichment of m6A-modified TRIM37 transcripts in control and ALKBH5 knockdown cells. (J) MeRIP assays followed by qPCR showing the enrichment of m.6A-modified TRIM37 transcripts in control and ALKBH5-OE cells. (K) TRIM37 mRNA stability was assessed by actinomycin D chase assay. The remaining TRIM37 mRNA levels were measured by qRT-PCR at the indicated time points after transcription inhibition in control versus ALKBH5-knockdown, and control versus ALKBH5-OE cells. (L) Dual luciferasereporter assay determined the relative luciferase activities in PDAC cells following the indicated transfection. (M) Effects of IGF2BP1 overexpression in MIA PaCa-2 cells on TRIM37 protein level. (N) Effects of IGF2BP1 overexpression in MIA PaCa-2 cells on TRIM37 mRNA level. (O) TRIM37 mRNA stability was assessed by actinomycin D chase assay. The remaining TRIM37 mRNA levels were measured by qRT-PCR at the indicated time points after transcription inhibition in control versus IGF2BP1-OE cells. The data are presented as means ± SD (n = 3), **P < 0.01

Fig. 9.

Fig. 9

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Schematic diagram illustrating the ALKBH5/IGF2BP1-TRIM37-RBMX axis in promoting PDAC progression

Discussion

In this study, we characterized TRIM37 as a critical oncoprotein in PDAC and elucidated a comprehensive regulatory axis that governs its expression and function. Our data demonstrate that TRIM37 is aberrantly overexpressed at the protein level in human PDAC tissues, and this overexpression serves as a potent indicator of poor prognosis. Through rigorous in vitro and in vivo functional studies, we unequivocally showed that TRIM37 promotes aggressive malignant behaviors, including proliferation, migration, invasion, stemness, and tumor growth. Mechanistically, we identified a novel pathway wherein TRIM37, an E3 ubiquitin ligase (Qin et al. 2024), targets the tumor suppressor RBMX for proteasomal degradation, thereby facilitating glycolytic reprogramming. Moreover, We demonstrated that TRIM37 is post-transcriptionally upregulated upon ALKBH5 loss, through an m6A-dependent mechanism in which IGF2BP1 binds and stabilizes TRIM37 mRNA. Collectively, these findings establish the ALKBH5/IGF2BP1-TRIM37-RBMX axis as a pivotal driver of PDAC pathogenesis.

Our findings position TRIM37 as a clinically relevant oncogenic marker in PDAC. Across the TCGA cohort and our independent cohort, TRIM37 mRNA and protein levels were consistently upregulated in tumor tissues, and higher TRIM37 expression was associated with worse OS and DFS. Functional analyses performed in our study clearly demonstrate that TRIM37 plays a critical oncogenic role in PDAC development, aligning with previous findings (Jiang et al. 2016). In vitro, genetic ablation of TRIM37 in high-TRIM37-expressing cell lines (ASPC-1, PANC-1) leads to the suppression of key oncogenic traits, including proliferation, migration, invasion, and stemness, whereas overexpression of TRIM37 in low-TRIM37-expressing cell lines (MIA PaCa-2, BxPC-3) enhances these traits. In vivo, TRIM37 knockdown significantly inhibited xenograft growth and prevented the formation of pulmonary nodules, confirming a tumor-intrinsic dependence. Together, these concordant gain- and loss-of-function data strongly support a causal role for TRIM37 in driving PDAC growth, metastatic potential, and cellular plasticity.

Our study elucidates the molecular mechanism by which TRIM37 drives PDAC progression, identifying a novel TRIM37-RBMX regulatory axis that modulates glycolytic metabolism. RBMX is an RNA-binding protein with tumor suppressor properties (Zheng et al. 2020). It has been demonstrated to inhibit tumor proliferation, migration, invasion, and clonogenicity in bladder cancer by interacting with hnRNP A1 to regulate PKM gene splicing (Yan et al. 2021). In hepatocellular carcinoma, RBMX downregulation suppresses tumor cell proliferation, migration, and invasion, and may also influence immune checkpoint inhibitor efficacy (Sheng et al. 2024). In pancreatic cancer, low RBMX expression correlates with advanced tumor stage, metastasis, and unfavorable prognosis (Alors-Pérez et al. 2024). We demonstrated that TRIM37 functions as an E3 ubiquitin ligase to directly bind and target the tumor suppressor RBMX for ubiquitin-mediated degradation. This post-translational regulation of RBMX protein stability is a key event, as evidenced by rescue experiments showing that RBMX ablation reversed the antiglycolytic and antitumor effects of TRIM37 knockdown. Collectively, these findings establish that TRIM37 promotes glycolytic reprogramming and malignant phenotypes in PDAC primarily through the suppression of RBMX, revealing a previously unrecognized link between ubiquitin signaling and metabolic reprogramming in this malignancy.

Numerous studies have confirmed that m6A modification plays a crucial role in cancers. For example, Cui et al. highlighted the critical role of IGF2BP3-mediated m6A modification in oral squamous cell carcinoma (Cui et al. 2025). In addition, under hypoxic conditions in breast cancer, HIF-1α–driven upregulation of the demethylase FTO has been reported to reduce the degradation of target mRNAs and activate the AKT/STAT3 signaling pathway (Wang et al. 2025). In prostate cancer, m6A modification has also been implicated in modulation of the p53 signaling pathway (Cheng et al. 2024). Based on these findings, we identified an m⁶A-dependent regulatory mechanism driving TRIM37 overexpression in pancreatic cancer. Our study elucidates the upstream regulatory mechanism underlying TRIM37 overexpression in PDAC. Previous studies have reported that ALKBH5 plays a crucial tumor-suppressive role in PDAC (Guo et al. 2020). We identified the RNA demethylase ALKBH5 as a key negative regulator of TRIM37. The ALKBH5-IGF2BP1 axis in PDAC tissues creates an environment conducive to TRIM37 mRNA stabilization through increased m6A methylation. The inverse correlation between ALKBH5 and TRIM37, combined with our mechanistic data from MeRIP and actinomycin D assays, strongly supports a model where ALKBH5-IGF2BP1 axis leads to hyper-methylation of TRIM37 mRNA, consequently enhancing its stability and translational output. This exemplifies the context-dependent nature of m6A modification and its significant role in oncogene regulation.

This study still has several limitations. First, the variety of animal models used in the present work could be further expanded. Owing to the constraints of time and experimental resources, patient-derived xenograft (PDX) models were not established in this study. Constructing such models will serve as a key direction for subsequent validation. Second, RBMX may not be the only target of TRIM37. Due to scope limitations, we focused on RBMX based on a hypothesis-driven rationale. In the future, other protein substrates could be systematically evaluated or screened. Finally, other m6A readers, including members of the YTHDF family, may also play context-dependent roles. Therefore, the precise functions of other m6A regulatory proteins merit further investigation.

In conclusion, our study unveils a well-integrated ALKBH5-IGF2BP1/TRIM37/RBMX signaling axis that is pivotal in the progression of PDAC. We identified TRIM37 as a central regulatory node, which is epi-transcriptionally controlled by ALKBH5/IGF2BP1, which facilitates glycolytic reprogramming through the proteasomal degradation of RBMX. This mechanistic pathway underscores the role of TRIM37 in PDAC metabolism and malignancy.

Supplementary information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 402 KB) (402.4KB, docx)

Acknowledgements

We thank BioRender for providing tools to create graphical abstract in this study.

Author contributions

D.W., Y.C., and G.C. conceived and designed the experiments. X.P. collected clinical samples. C.Y., X.L. and Y.Z. performed the experiments. C.Y., X.L., Y.Z., and J.C. analyzed the data. D.W., Y.C., and G.C. supervised the whole experimental work and revised the manuscript. C.Y., X.L. and Y.Z. wrote the paper.

Funding

This work was supported by the National Natural Science Foundation of China (No.82305403).

Data availability

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

Declarations

Ethics approval and consent to participate

The procedures for care and use of animals were approved by the Ethics Committee of the Second Xiangya Hospital (No.20251279) and all applicable institutional and governmental regulations concerning the ethical use of animals were followed.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Cheng Yan, Xuan Li and Ying Zhao contributed equally to this work.

Contributor Information

Daichao Wu, Email: wudaichao@usc.edu.cn.

Yabin Chang, Email: cybyyy@163.com.

Guodong Chen, Email: chenguodong@usc.edu.cn.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary file1 (DOCX 402 KB) (402.4KB, docx)

Data Availability Statement

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

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