Overcoming distant metastasis stands as a paramount challenge in enhancing the outcomes of breast cancer treatments. Thus, delving deeper into comprehending the intricate mechanisms underlying breast cancer metastasis becomes imperative, offering potential avenues for pioneering therapeutic approaches. PRMT6, an arginine N-methyltransferase, possesses the ability to methylate both histone and non-histone proteins. It has been reported that methylation of non-histone proteins impacts their cellular localization, stability, and activation, consequently influencing tumor progression. However, the extent to which PRMT6-mediated non-histone protein methylation influences cancer cell metastasis, particularly in the context of breast cancer, remains elusive. In this study, we established that PRMT6 exerted a positive regulatory influence on breast cancer metastasis through both in vivo and in vitro experiments. Mechanistically, we innovatively revealed that PRMT6 asymmetrically di-methylated STAT3 at arginine 729 (STAT3 R729me2a). This modification proved indispensable for STAT3’s membrane localization, its interaction with JAK2, STAT3 Y705 phosphorylation, and PRMT6-driven cancer cell metastasis. From a clinical perspective, we unearthed the promising potential of STAT3 R729me2a as a robust prognostic marker for predicting the overall survival time of breast cancer patients. In terms of therapeutic intervention, we demonstrated the significant capability of the PRMT6 inhibitor, EPZ020411, to curtail breast cancer metastasis both in vivo and in vitro. In sum, our study unveils the pivotal biological role of PRMT6-mediated STAT3 R729me2a in breast cancer metastasis and underscores the prospective utility of PRMT6 inhibitors as effective therapeutic strategies against STAT3-driven metastatic breast cancer.

Background: Upregulation of CXCL8 (C-X-C motif ligand 8) in tumor cells has been reported in several types of cancer, and it correlates with a poor prognosis. However, the role of CXCL8 in glioma progression remains unknown. Materials and methods: In this study, we examined CXCL8 expression levels in human glioma cell lines and in sixteen human gliomas with different grades. The molecular role of CXCL8 in glioma cells was investigated using quantitative polymerase chain reaction (qRT-PCR) assays, Western blotting, CCK-8 assays, EdU assays, colony formation assays, Transwell migration and invasion assays. Results: We found that high expression levels of CXCL8 were positively associated with progression and poor prognosis in human glioma. Mechanistically, CXCL8 promoted the epithelial-mesenchymal transition (EMT) in glioma cells by activating the JAK/STAT1/HIF-1α/Snail signaling pathway. Conclusion: Taken together, our data provide a plausible mechanism for CXCL8-modulated glioma progression, which suggests that CXCL8 may represent a potential therapeutic target in the prevention and treatment of gliomas.

Background: Advanced triple-negative breast cancer (TNBC) is prone to brain metastasis (BrM). The precise molecular mechanism responsible for this phenomenon has not yet been completely established, so it is vital to comprehend the molecular mechanism behind it. Methods: The protein chip analysis was conducted to identify any abnormal UBE2T protein expression in TNBC, especially BrM. Here, we used public databases and bioinformatics analysis as well as clinical samples from different cohorts to investigate the interrelationship between UBE2T/CDC42/CD276. This predicted relationship was then repeatedly validated using different in vivo and in vitro experimental methods. Additionally, multiple experimental approaches were implemented, encompassing western blotting, Co-IP, GST pull-down, flow cytometry, mass spectrometry, immunofluorescence, immunohistochemistry, and qRT-PCR to reveal the molecular mechanism of UBE2T-mediated immune escape and BrM. Results: Our results indicate that expressed at elevated levels in breast cancer, UBE2T is negatively linked to patient prognosis, especially in BrM of TNBC. Data from clinical samples from our different cohorts and TCGA indicate a significant correlation between UBE2T and immunosuppression. Mechanistically, UBE2T directly interacts with CDC42, promoting its K48-linked polyubiquitination and proteasomal degradation, thereby inhibiting CDC42 from degrading CD276 via the autophagy-lysosomal pathway, indirectly upregulating CD276 and thereby impairing the CD8⁺ T cells function, ultimately mediating tumor immune escape and BrM. Finally, animal experimental results also showed that inhibition of UBE2T elevated the TNBC sensitivity to immune checkpoint CD276 blockade and inhibited BrM of TNBC. Conclusions: In conclusion, our results indicate a new mechanism whereby UBE2T-mediated ubiquitination positively controls the UBE2T/CDC42/CD276 axis to upregulate tumor cell expression of CD276 and thereby impair CD8⁺ T cells function, ultimately leading to tumor cell immune escape and BrM.

Antigen loss is a major mechanism of resistance to immunotherapy. MIC-A/B are stress-inducible ligands expressed by tumor cells that activate NKG2D on cytotoxic immune cells and mediate NKG2D-dependent tumor cell killing, yet the mechanisms underlying their reduced expression in glioma remain unclear. Using single-cell RNA sequencing and spatial transcriptomics, we investigated ectopic MIC-A/B in mouse glioma and identified USP14 as a key regulator through deubiquitinase screening. Proteomic, coimmunoprecipitation, chromatin immunoprecipitation, immunofluorescence, and ubiquitination assays characterized the interactions among USP14, PARP1, and nuclear factor, interleukin 3 regulated (NFIL3), while an intracranial tumor model combined USP14 inhibition and immunotherapy to evaluate effects on tumorigenesis and antitumor immunity. We found that MIC-A/B increased CD8 ⁺ T cell infiltration and reversed exhaustion and that USP14 stabilized PARP1 via K63-linked deubiquitination at lysine-653, reducing NFIL3 binding to the MIC-A/B promoter through poly(ADP-ribosyl)ation. Inhibition of USP14 activated CD8 ⁺ T cells in a MIC-A/B–NKG2D–dependent, antigen-independent manner and synergized with PD1 blockade to prolong survival and enhance antitumor immunity. Clinical glioma specimens showed that the USP14 overexpression was correlated with PARP1 and dysfunctional CD8 ⁺ T cell infiltration. These results demonstrate that USP14 inhibition restores MIC-A/B–mediated CD8 ⁺ T cell activation, reverses immune exhaustion, and represents a promising strategy to enhance glioma immunotherapy.

Background: Nicotinamide adenine dinucleotide (NAD+) metabolism is involved in a series of cancer pathogenesis processes, and is considered a promising therapeutic target for cancer treatment. However, a comprehensive analysis of NAD+ metabolism events on immune regulation and cancer survival has not yet been conducted. Here, we constructed a prognostic NAD+ metabolism-related gene signature (NMRGS) associated with immune checkpoint inhibitor (ICI) efficacy in glioma.Methods: 40 NAD+ metabolism-related genes (NMRGs) were obtained from the Reactome database and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Glioma cases with transcriptome data and clinical information were obtained from Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). NMRGS was constructed based on the calculated risk score using univariate analysis, Kaplan–Meier analysis, multivariate Cox regression, and nomogram. This NMRGS was verified in training (CGGA693) and validation (TCGA and CGGA325) cohorts. The immune characteristics, mutation profile, and response to ICI therapy were subsequently analyzed for different NMRGS subgroups.Results: Six NAD+ metabolism-related genes, including CD38, nicotinamide adenine dinucleotide kinase (NADK), nicotinate phosphoribosyltransferase (NAPRT), nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3), poly(ADP-Ribose) polymerase family member 6 (PARP6), and poly(ADP-Ribose) polymerase family member 9 (PARP9), were ultimately used to construct a comprehensive risk model for glioma patients. Patients in the NMRGS-high group showed a poorer survival outcome than those in the NMRGS-low group. The area under curve (AUC) indicated that NMRGS has good potential in glioma prognostic prediction. A nomogram with improved accuracy was established based on independent prognostic factors (NMRGS score, 1p19q codeletion status, and WHO grade). Furthermore, patients in the NMRGS-high group showed a more immunosuppressive microenvironment, higher tumor mutation burden (TMB), higher human leucocyte antigen (HLA) expression and a more therapeutic response to ICI therapy.Conclusions: This study constructed a prognostic NAD+ metabolism-related signature associated with the immune landscape in glioma, which can be used for guiding individualized ICI therapy.

Background: There is growing evidence that aberrant expression of FAM72A contributes to biological dysfunction, especially mitochondrial dysfunction. However, its role in most tumors remains unclear, especially in glioma.