Glioblastoma is notoriously invasive and resistant to programmed cell death (PCD). Mitochondria serve as the central hub integrating multiple death signals, thereby orchestrating both apoptotic and non‑apoptotic PCD. Therefore, investigating how mitochondria‑associated PCD operates in GBM becomes particularly critical for exploring potential therapeutic targets. In this study, we discovered that the mitochondria-associated programmed cell death (MPCD) gene, cytochrome c oxidase subunit 5B (COX5B)—a nuclear-encoded regulator of mitochondrial complex IV, promotes the growth of GBM by regulating mitochondrial function and inhibiting XAF1-related apoptosis. By integrating single-cell and bulk transcriptomics, we identified glioma-enriched MPCD genes and developed a machine-learning prognostic model with robust predictive performance. COX5B emerged as a central hub, upregulated in GBM, with high expression correlating with poor survival. Utilizing a multi-disciplinary approach combining immunohistochemistry (IHC), immunofluorescence (IF), quantitative PCR, western blotting, transmission electron microscopy (TEM) and flow cytometry, we demonstrate that COX5B knockdown impaired mitochondrial integrity, triggering cytosolic release of cytochrome c and mtDNA, elevating ROS, collapsing membrane potential, and causing cristae loss and organelle swelling. These mitochondrial insults activated intrinsic apoptosis via Bax/caspase 9/3 and Bcl 2 downregulation, while cytosolic mtDNA induced the JAK-STAT1/XAF1 signaling axis. XAF1 co-silencing partially rescued proliferation, migration, and apoptosis defects. In vivo, COX5B depletion suppressed xenograft growth and promoted apoptosis, effects partially reversed by XAF1 co-depletion. Our findings uncovers a novel COX5B-STAT1-XAF1 cascade linking mitochondrial dysfunction, cytochrome c/mtDNA release, and transcriptional apoptosis control, highlighting COX5B as a promising therapeutic target in GBM.

BACKGROUND:Glioblastoma multiforme (GBM) is an incurable malignancy characterized by invasiveness and resistance to treatment. Dihydrolipoamide dehydrogenase (DLD), a metabolic redox enzyme, plays a pivotal role in key metabolic processes. Recent studies have increasingly highlighted the involvement of DLD in various cancers; however, its role in GBM remains underexplored. AIM:This study aimed to delineate the expression, regulation, and oncogenic function of DLD in glioma. METHODS:Expression analysis of DLD in GBM tissues, in vitro and in vivo functional assays, and mechanistic studies focusing on transcriptional regulation by YY1/EP300 and lncRNA CRNDE, as well as DLD-EphA2 interaction and PI3K/AKT/mTOR signaling. RESULTS:This study reveals that DLD is aberrantly overexpressed in GBM, with its expression level negatively correlating with clinical prognosis in patients with GBM. Both in vitro and in vivo analyses confirm that DLD acts as an oncogene in GBM, promoting cell proliferation, migration, and invasion. Mechanistically, DLD expression is regulated by the transcription factor YY1, with the coactivator EP300 interacting with YY1 to further enhance DLD expression. Moreover, the long non-coding RNA CRNDE facilitates YY1-EP300 interaction, thereby promoting DLD transcription. DLD also directly interacts with EphA2, influencing its phosphorylation at the S897 site and modulating the PI3K/AKT/mTOR pathway, which in turn supports its biological activities in GBM. CONCLUSIONS:DLD functions as an oncogene in GBM and represents a potential biomarker and therapeutic target.

Colorectal carcinoma (CRC) ranks as the second leading cause of cancer mortality worldwide. However, the mechanisms underlying CRC progression and metastasis, remain unclear. Our current research has identified that TATA-binding protein-associated factor-1 (TAF1), also as a lysine acetyltransferase, is frequently upregulated in CRC. Survival analysis has indicated that patients whose tumors expressed high TAF1 levels had poorer outcomes. Additionally, TAF1 overexpression fosters CRC proliferation, colorectal cancer stem-like cell stemness (CRCSC), and metastasis. Mechanistically, we first reported that lysine β-hydroxybutyrylation (Kbhb) modification of KCTD9 at K123 and K129, mediated by TAF1, facilitates the binding of TRIM21, thereby mediating the ubiquitination degradation of KCTD9. This event consequently suppresses KCTD9 protein expression to activate Notch signaling pathway, ultimately enhancing CRC progression and metastasis. Moreover, the concomitant upregulation of TAF1 and KCTD9 Kbhb serves as a poor prognostic factor for metastatic CRC patients. Taken together, our findings bridge the newly identified Kbhb modification dependent regulatory mechanism that modulates the anticancer function of KCTD9, and provided insight into potential strategies for targeting epigenetic factor and combating the KCTD9 inactive-driven CRC metastasis.

BACKGROUND: Glioblastoma (GBM) is a highly aggressive brain tumour with a poor prognosis. Mitochondrial dysfunction, including changes in oxidative phosphorylation, reactive oxygen species (ROS) production, and cristae organisation, plays a key role in the progression of GBM. However, the role of mitochondrial protein complexes in GBM biology is poorly understood. METHODS: Bioinformatics analyses of GBM datasets and mitochondrial complexome profiling (‘MitCOM’) identified mitochondrial protein complex genes (MitCOMGs) with prognostic significance. A six-gene prognostic model was constructed using least absolute shrinkage and selection operator (LASSO) regression and validated in independent cohorts. GLUD1, the most significant gene, was further validated through in vitro assays, including Blue Native PAGE, metabolomic profiling, and various cell assays. RESULTS: GLUD1 expression was downregulated in GBM and associated with poor survival. Functional studies showed that GLUD1 regulates mitochondrial crista organisation and metabolic reprogramming. GLUD1 overexpression disrupted mitochondrial integrity, impaired respiratory chain complex assembly, and reduced adenosine triphosphate production. Metabolomic profiling revealed altered amino acid metabolism and tricarboxylic acid cycle intermediates that inhibited GBM cell proliferation and invasion. CONCLUSIONS: GLUD1 is a key mitochondrial regulator in GBM, and its downregulation contributes to tumour progression through mitochondrial dysfunction and metabolic reprogramming. The six-gene MitCOMG model offers robust prognostic value and identified GLUD1 as a potential therapeutic target for GBM.

Purpose Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric malignancy of the brainstem with a lack of effective therapeutic options. This study assesses the efficacy and safety of adding nimotuzumab to temozolomide (TMZ) chemoradiation therapy for newly diagnosed pediatric DIPG. Methods and Materials We conducted an open-label, single-arm, prospective, multicenter study involving children aged 3-15 years with histologically or radiographically confirmed DIPG from April 3, 2021 to April 13, 2023. Nimotuzumab (150 mg/m2/wk) was administered concurrently with local radiation therapy (54 Gy/30 f) and TMZ (75 mg/m2/d) for 6 weeks, followed by adjuvant TMZ (150-200 mg/m2 for 5 consecutive days of a 28-day cycle for 6 cycles) and nimotuzumab (150 mg/m2 biweekly until to disease progression). The primary endpoint was objective response rate (ORR). The secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. Adverse events were summarized using descriptive statistics. Results Of 48 enrolled patients, with a median age of 7 years (4-14), 28 (58.3%) were histologically confirmed, and 25 (89.3%) had H3K27M mutations. With a median follow-up of 26.5 months (95% CI, 14.6-not applicable), the ORR was 37.5%; the median OS and PFS were 10.5 (8.3-11.2) and 7.8 (5.1-8.4) months; and 1-year OS and PFS rates were 33.3% and 26.9%, respectively. Multivariate analysis showed that a partial response and no steroid use were associated with favorable OS. Distant metastasis was observed in 7 patients (14.6%). The most common grade ≥ 3 treatment-related adverse events were leukopenia (27.1%), lymphopenia (27.1%), and neutropenia (25.0%). Conclusions Adding nimotuzumab to chemoradiation therapy is feasible, with ORR and survival rates favorably comparable with previous data in pediatric DIPG, despite not meeting the prespecified statistical significance for improved ORR compared with historical data. The overall safety profile was manageable, with no new safety concerns.

Low-grade gliomas (LGG) are a heterogeneous category of brain tumors characterized by a variable clinical course, frequently associated with unfavorable prognosis and therapeutic challenges. Understanding the molecular mechanisms underlying LGG progression is crucial for improving prognosis and therapeutic strategies. This study integrates single-cell RNA sequencing and bioinformatics to explore the role of METCGs (mitochondrial electron transport chain genes) in LGG and construct a predictive model for prognosis, and through in vitro experiments, the feasibility of this model was validated. We analyzed 5,691 cells and 22,947 genes from the GSE117891 dataset. Using cell marker genes from the CellMarker 2.0 database and classical markers, we identified four distinct cell types: oligodendrocytes, T cells, astrocytes, and microglial cells. The METCGs profiles were calculated using various algorithms, including AUCell, UCell, ssGSEA, and others. Differentially expressed genes (DEGs) were identified and enriched for relevant pathways. Machine learning algorithms were employed to construct a prognostic risk model based on five selected METCGs. The model was validated using independent LGG cohorts. Biological pathway analyses, immune infiltration profiles, and potential drug targets were also explored. To validate the reliability of this model through experiments, functional experiments, including Blue native Page (BN-Page), western blotting, immunofluorescence, and cell viability assays, were conducted to validate SDHB expression and its role in LGG progression. Astrocytes exhibited the highest METCG scores, indicating their central role in mitochondrial energy regulation. The prognostic model, constructed using the StepCox[forward] + plsRcox approach, included five genes: SDHB, SDHC, SLC25A27, UQCRB, and NDUFA13. The model demonstrated high prognostic accuracy with an average C-index of 0.67 and successfully stratified LGG patients into low- and high-risk groups. High-risk patients had worse survival outcomes, with significant differences observed in KEGG pathways, immune infiltration, and metabolic processes. The low-risk group exhibited higher immune cell infiltration, including follicular helper T and monocyte cells. AZD1208_1449 was identified as a potential drug targeting high-risk patients. Additionally, SDHB expression was significantly higher in LGG cells, and knockdown of SDHB inhibited cell proliferation and invasion, supporting its role in tumor progression. This study provides a comprehensive analysis of METCGs in LGG and develops a robust prognostic model for patient stratification. SDHB, a key subunit of Complex II, plays a crucial role in mitochondrial function and tumor progression. Our findings suggest that he high expression of SDHB in LGG contributes to maintaining elevated SDH and Complex II activity, ensuring the structural and functional integrity of mitochondrial ETC complexes. This supports the high ROS production and MMP required for the rapid growth of LGG, thereby promoting its proliferation and invasion. Thus, targeting SDHB and its associated pathways could offer new therapeutic avenues for LGG treatment.

Complex crosstalk occurs between protein and nucleic acid modifications, with lactylation, an emerging post-translational modification (PTM), being implicated in tumor progression. However, the mechanisms mediating the crosstalk between lactylation and RNA modifications and their roles in disease pathogenesis remain largely unresolved. In this review, we summarize current advances in the regulatory interactions between lactylation and RNA modifications, explore their functional implications in cancer biology, and discuss the therapeutic potential of targeting these modifications individually or in combination. This work aims to provide a comprehensive overview of their mechanistic involvement in cancer and to inform novel strategies for precision-targeted therapy.

Brainstem gliomas (BSG) is a highly malignant central nervous system childhood tumors with 5-year survival rate <10%. Metabolism during radiotherapy is a dynamic and precisely programmed process, improving clinical outcomes and guiding therapy decisions of BSG. Here we construct diagnostic and prognostic assays of BSG via circulating metabolites based on both cross-sectional study and longitudinal cohort study with 106 BSG patients. We employ nanoparticle enhanced laser desorption/ionization mass spectrometry to characterize static and dynamic snapshots of metabolites during BSG radiotherapy. We show that this serological tool reaches the area under the curve of 0.933 for BSG diagnosis in an independent blind test and predicts risk of patients with significant differences (p < 0.05) in prognostic outcomes. We further identify eight distinct temporal patterns of metabolite regulation associated with radiotherapy responses and tracked the metabolic trajectory via dynamic metabolic snapshots throughout radiotherapy process. If further validated, this framework could be extended to derive comprehensive metabolic pictures for cancers including but not limited to BSG.

Medulloblastoma (MB) is a malignant brain tumour that is highly common in children and has a tendency to spread to the brain and spinal cord. MB is thought to be a metabolically driven brain tumour. Understanding tumour cell metabolic patterns and characteristics can provide a promising foundation for understanding MB pathogenesis and developing treatments. Here, by analysing RNA-seq data of MB samples from the Gene Expression Omnibus (GEO) database, 12 differentially expressed metabolic-related genes (DE-MRGs) were chosen for the construction of a predictive risk score model for MB. This model demonstrated outstanding accuracy in predicting the outcomes of MB patients and served as a standalone predictor. An evaluation of functional enrichment revealed that the risk score showed enrichment in pathways related to cancer promotion and the immune response. In addition, a high risk score was an independent poor prognostic factor for MB in patients with different ages, sexes, metastasis stages and subgroups (SHH and Group 4). Consistently, the metabolic enzyme ornithine decarboxylase (ODC1) was upregulated in MB patients with poor survival time. Inhibition of ODC1 in primary and metastatic MB cell lines decreased cell proliferation, migration and invasion but increased immune infiltration. This study could aid in identifying metabolic targets for MB as well as optimizing risk stratification systems and individual treatment plans for MB patients via the use of a metabolism-related gene prognostic risk score signature.

Abstract BACKGROUND Newly diagnosed pediatric DIPG is a fetal disease with a poor prognosis and lacks of effective treatments. Multiple studies have demonstrated that the median survival time for patients is less than one year. A single-armed, prospective, multicenter study was conducted to evaluate the efficacy and safety of adding nimotuzumab to concurrent chemoradiotherapy for the treatment of newly diagnosed pediatric DIPG. METHODS Patients were 3-15 years old, histologically or imaging confirmed newly diagnosed DIPG, Lansky score ≥ 60, and at least one measurable lesion. Totally 48 patients were enrolled. Nimotuzumab (150mg/m2/w) concurrent chemoradiotherapy (Temozolomide: 75mg/m2 per day. Radiotherapy: 54Gy/30f) were administered for 6 weeks following a maintenance treatment (Nimotuzumab: 150mg/m2 biweekly. Temozolomide: 150-200mg/m2 per day for 5 days every 28 day). The primary endpoint was ORR, with secondary endpoints including 1-year OS rate, PFS and safety. RESULTS Between Apr 3, 2021 and Apr 13, 2023, a total of 48 patients were enrolled with a median age of 7 years old, in which 20 patients radiologically diagnosed DIPG, 28 patients histopathologically confirmed DIPG with 25 (89.3%) had H3K27M mutation. The median follow-up was 15.2 months. The ORR was 31.3% (95%CI, 18.66%-46.25%), mOS was 10.35 months, 1-year OS rate was 27.4% (95%CI, 14.73%-41.73%), mPFS was 6.93 months, and 1-year PFS was 9.5% (95%CI, 2.46%-22.56%). Eight patients (16.7%) experienced grade 3 or above ADRs. The most common toxicities were neutropenia (40%), leukopenia (25.0%), thrombocytopenia (25.0%). anemia (5.0%), flank pain (5.0%). CONCLUSIONS Nimotuzumab combined with concurrent chemoradiotherapy showed survival benifit for newly diagnosed pediatric DIPG patients with tolerable toxicity.

Importance:High-grade gliomas (HGGs) constitute the most common and aggressive primary brain tumor, with 5-year survival rates of 30.9% for grade 3 gliomas and 6.6% for grade 4 gliomas. The add-on efficacy of interferon alfa is unclear for the treatment of HGG. Objectives:To compare the therapeutic efficacy and toxic effects of the combination of temozolomide and interferon alfa and temozolomide alone in patients with newly diagnosed HGG. Design, Setting, and Participants:This multicenter, randomized, phase 3 clinical trial enrolled 199 patients with newly diagnosed HGG from May 1, 2012, to March 30, 2016, at 15 Chinese medical centers. Follow-up was completed July 31, 2021, and data were analyzed from September 13 to November 24, 2021. Eligible patients were aged 18 to 75 years with newly diagnosed and histologically confirmed HGG and had received no prior chemotherapy, radiotherapy, or immunotherapy for their HGG. Interventions:All patients received standard radiotherapy concurrent with temozolomide. After a 4-week break, patients in the temozolomide with interferon alfa group received standard temozolomide combined with interferon alfa every 28 days. Patients in the temozolomide group received standard temozolomide. Main Outcomes and Measures:The primary end point was 2-year overall survival (OS). Secondary end points were 2-year progression-free survival (PFS) and treatment tolerability. Results:A total of 199 patients with HGG were enrolled, with a median follow-up time of 66.0 (95% CI, 59.1-72.9) months. Seventy-nine patients (39.7%) were women and 120 (60.3%) were men, with ages ranging from 18 to 75 years and a median age of 46.9 (95% CI, 45.3-48.7) years. The median OS of patients in the temozolomide plus interferon alfa group (26.7 [95% CI, 21.6-31.7] months) was significantly longer than that in the standard group (18.8 [95% CI, 16.9-20.7] months; hazard ratio [HR], 0.64 [95% CI, 0.47-0.88]; P = .005). Temozolomide plus interferon alfa also significantly improved median OS in patients with O6-methylguanine-DNA methyltransferase (MGMT) unmethylation (24.7 [95% CI, 20.5-28.8] months) compared with temozolomide (17.4 [95% CI, 14.1-20.7] months; HR, 0.57 [95% CI, 0.37-0.87]; P = .008). Seizure and influenzalike symptoms were more common in the temozolomide plus interferon alfa group, with 2 of 100 (2.0%) and 5 of 100 (5.0%) patients with grades 1 and 2 toxic effects, respectively (P = .02). Finally, results suggested that methylation level at the IFNAR1/2 promoter was a marker of sensitivity to temozolomide plus interferon alfa. Conclusions and Relevance:Compared with the standard regimen, temozolomide plus interferon alfa treatment could prolong the survival time of patients with HGG, especially the MGMT promoter unmethylation variant, and the toxic effects remained tolerable. Trial Registration:ClinicalTrials.gov Identifier: NCT01765088.

[This corrects the article DOI: 10.3389/fonc.2020.573318.].

Background Nervus intermedius (NI) injuries are not given enough attention by neurosurgeons during vestibular schwannoma (VS) surgery. Preservation of NI function is essential for the integrity and continuity of the facial nerve, although this can be challenging. We identified the risk factors for NI injury and proposed our experience for optimizing NI preservation based on our cases. Methods We retrospectively analyzed clinical data from a consecutive series of 127 patients with VS who underwent microsurgery via the retrosigmoid approach from 2017 to 2021 at our institution. The baseline characteristics of the patients were collected from the medical records, and the incidence of NI dysfunction symptoms was obtained by outpatient and online video follow-up 6 months after surgery. The surgical procedures and techniques used were described in detail. The data were analyzed in relation to sex, age, tumor location (left or right), Koos grading scale, internal acoustic canal (IAC) invasion (TFIAC Classification), brainstem adhesion, tumor characteristics (cystic or solid), tumor necrosis, and preoperative House–Brackmann (HB) grading by univariate and multivariate analyses. Results Gross tumor removal was achieved in 126 (99.21%) patients. Subtotal removal was performed on one patient (0.79%). Twenty-three of our cases exhibited facial nerve palsy preoperatively; 21 patients had HB grade II facial palsy, and two had HB grade III. Two months after surgery, 97 (76.38%) patients had normal function of the motor portion of the facial nerve; 25 (19.69%) patients had HB Grade II facial palsy, five had Grade III (3.94%), and zero (0%) had Grade IV. Postoperatively, 15 patients experienced newly gained dry eyes (11.81%), whereas 21 cases of lacrimal disturbances (16.54%), nine of taste disturbances (7.09%), seven of xerostomia (5.51%), five of nasal hypersecretions (3.94%), and seven of hypersalivation (5.51%) were identified in our cases. Univariate and multivariate analyses revealed that the Koos grading scale and tumor characteristics (solid or cystic) were correlated with NI injury (p <0.01). Conclusion The data in this study demonstrate that although the motor function of the facial nerve is well preserved, NI disturbance is still common after VS surgery. Maintaining the integrity and continuity of the facial nerve is key to NI function. Performing bidirectional and subperineurium dissection based on even and adequate debulking is beneficial for NI preservation in VS surgery. Higher Koos grading and cystic characteristics of VS are associated with postoperative NI injuries. These two parameters can be used to guide the delineation of surgical strategy and predict the prognosis of NI function preservation.

Muscle diseases are closely related to autophagy disorders. Studies of autophagy inhibition indicated the importance of autophagy in muscle regeneration, while activation of autophagy can restore muscle function in some myopathies. Previous studies have revealed that mutations in the MYOT gene may lead to several kinds of hereditary myopathies. However, whether the autophagy played a crucial role in hereditary myopathy caused by MYOT mutations was still not clear. In this study, we established the MYOT knockdown human skeletal muscle cell models (HSkMCs) by small interfering RNA. Real-time PCR and Western blot studies found that the expression of p62 and LC3B-II was decreased dramatically, which suggested that silencing MYOT expression may regulate the autophagy in HSkMCs. Further immunofluorescence study on Ad-mCherry-GFP-LC3B adenovirus transfection and monodansylcadaverine (MDC) staining revealed that knocking down the expression of MYOT may inhibit the autophagy. Next, we used the autophagy inducer Earle’s balanced salt solution (EBSS) and late-autophagy inhibitor bafilomycin A1 (BAF A1) to treat the HSkMCs, respectively, and found that silencing MYOT expression can inhibit the activation of autophagy by EBSS and aggravate the inhibition of autophagy by BAF A1. Finally, we also found that silencing MYOT expression can downregulate the expression of ATG7 and ATG5, two important autophagy regulatory molecules. Hence, our study may first reveal that knocking down the expression of MYOT may inhibit the autophagy. Hereditary myopathies caused by MYOT mutations may partly result from the inhibition of autophagy in HSkMCs.

High-grade meningioma has an unsatisfactory outcome despite surgery and postoperative radiotherapy; however, the factors driving its malignancy and recurrence remain largely unknown, which limits the development of systemic treatments. Single-cell RNA sequencing (scRNA-Seq) technology is a powerful tool for studying intratumoral cellular heterogeneity and revealing the roles of various cell types in oncogenesis. In this study, scRNA-Seq is used to identify a unique initiating cell subpopulation (SULT1E1(+)) in high-grade meningiomas. This subpopulation modulates the polarization of M2-type macrophages and promotes meningioma progression and recurrence. A novel patient-derived meningioma organoid (MO) model is established to characterize this unique subpopulation. The resulting MOs fully retain the aggressiveness of SULT1E1(+) and exhibit invasiveness in the brain after orthotopic transplantation. By targeting SULT1E1(+) in MOs, the synthetic compound SRT1720 is identified as a potential agent for systemic treatment and radiation sensitization. These findings shed light on the mechanism underlying the malignancy of high-grade meningiomas and provide a novel therapeutic target for refractory high-grade meningioma.

Additional file 8: Table S3. The 201 DE-MRGs between neoplatstic and non-neoplastic cells.

神经外科是研究脑、脊髓的一门学科,以神经系统解剖为基础.由于其专业知识抽象、临床操作技能复杂,使得专业知识不易理解和掌握、临床思维难以建立,易使学生产生厌学情绪.因此,如何提高学生对神经外科专业知识的理解及掌握、如何建立临床思维是教师需要解决的问题.多元立体式教学法不仅可以使学生提高对神经外科专业知识学习的兴趣、提高临床操作技能,而且可以完善临床思维.

BACKGROUND:Glioblastoma (GBM) is the most common primary malignant brain tumor that leads to lethality. Several studies have demonstrated that mitochondria play an important role in GBM and that mitochondria-related genes (MRGs) are potential therapeutic targets. However, the role of MRGs in GBM remains unclear.METHODS:Differential expression and univariate Cox regression analyses were combined to screen for prognostic differentially-expressed (DE)-MRGs in GBM. Based on LASSO Cox analysis, 12 DE-MRGs were selected to construct a risk score model. Survival, time dependent ROC, and stratified analyses were performed to evaluate the performance of this risk model. Mutation and functional enrichment analyses were performed to determine the potential mechanism of the risk score. Immune cell infiltration analysis was used to determine the association between the risk score and immune cell infiltration levels. CCK-8 and transwell assays were performed to evaluate cell proliferation and migration, respectively. Mitochondrial reactive oxygen species (ROS) levels and morphology were measured using a confocal laser scanning microscope. Genes and proteins expression levels were investigated by quantitative PCR and western blotting, respectively.RESULTS:We identified 21 prognostic DE-MRGs, of which 12 DE-MRGs were selected to construct a prognostic risk score model for GBM. This model presented excellent performance in predicting the prognosis of patients with GBM and acted as an independent predictive factor. Functional enrichment analysis revealed that the risk score was enriched in the inflammatory response, extracellular matrix, and pro-cancer-related and immune related pathways. Additionally, the risk score was significantly associated with gene mutations and immune cell infiltration in GBM. Single-stranded DNA-binding protein 1 (SSBP1) was considerably upregulated in GBM and associated with poor prognosis. Furthermore, SSBP1 knockdown inhibited GBM cell progression and migration. Mechanistically, SSBP1 knockdown resulted in mitochondrial dysfunction and increased ROS levels, which, in turn, increased temozolomide (TMZ) sensitivity in GBM cells by enhancing ferroptosis.CONCLUSION:Our 12 DE-MRGs-based prognostic model can predict the GBM patients prognosis and 12 MRGs are potential targets for the treatment of GBM. SSBP1 was significantly upregulated in GBM and protected U87 cells from TMZ-induced ferroptosis, which could serve as a prognostic and therapeutic target/biomarker for GBM.

Smad nuclear-interacting protein 1 (SNIP1) is a transcription repressor related to the TGF-β signaling pathway and associates with c-MYC, a key regulator of cell proliferation and tumor development. Currently, the mechanism by which SNIP1 regulates tumorigenesis and cancer metastasis is unknown. Here, we identify that SNIP1 is a non-histone substrate of lysine methyltransferase KMT5A, which undergoes KMT5A-mediated mono-methylation to promote breast cancer cell growth, invasion and lung metastasis. Mechanistically, we show KMT5A-mediated K301 methylation of SNIP1 represents a sensing signal to release histone acetyltransferase KAT2A and promotes the interaction of c-MYC and KAT2A, and the recruitment of c-MYC/KAT2A complex to promoter of c-MYC targets. This event ultimately inhibits the Hippo kinase cascade to enhance triple-negative breast cancer (TNBC) metastasis by transcriptionally activating MARK4. Co-inhibition of KMT5A catalytic activity and YAP in TNBC xenograft-bearing animals attenuates breast cancer metastasis and increases survival. Collectively, this study presents an KMT5A methylation-dependent regulatory mechanism governing oncogenic function of SNIP1.