Numerous diseases have been connected to protein arginine methylations mediated by protein arginine methyltransferase 5 (PRMT5). Clinical investigations of the PRMT5-specific inhibitor GSK3326595 are currently being conducted, and the results are promising for preventing cancers. However, the detailed mechanism of PRMT5 promoting colorectal cancer (CRC) malignant progression remains unclear. Here, we found that PRMT5 directly catalyzes AlkB homologue 5 (ALKBH5) symmetric dimethylation at the R316 residue (meR316-ALKBH5), which enhances TRIM28-mediated ALKBH5 ubiquitination degradation. Then, an ALKBH5 decrease attenuates ALKBH5-mediated m6A demethylation on the CD276 transcript 3′ untranslated region, which increases CD276 messenger RNA stability and its expression in CRC cells. Furthermore, a CD276 expression increase facilitates CRC immune evasion by inhibiting cytotoxic T-cell functions. Moreover, we revealed that PRMT5-mediated meR316-ALKBH5 activates CD276 transcription by increasing its messenger RNA m6A modification to increase CRC immune evasion in vitro and in vivo. Furthermore, we consistently showed a strong association between meR316-ALKBH5 and poor outcomes in patients with CRC. Finally, we demonstrated that combining an anti-PD1 antibody with the PRMT5 inhibitor GSK3326595 markedly halts the progression of CRC. Our findings could serve as a basis for the development of a PRMT5–meR316-ALKBH5–CD276 axis-targeting treatment approach for CRC.

Lipid-peroxidation-driven ferroptosis represents a vital mode of regulated cell death increasingly recognized for its role in cancer therapy. Lipid metabolism plays a crucial role in determining the vulnerability of cells to ferroptosis, particularly in cancer cells. The biosynthesis and remodeling of polyunsaturated fatty acid-phosphatidylethanolamine in cell membranes rely heavily on the activity of acyl-CoA synthetase family member 4 (ACSL4). However, the regulatory mechanisms governing ACSL4 expression in renal cell carcinoma (RCC) remain unclear. In this study, we screened a library of 765 epigenetic compounds to identify novel regulators of ferroptosis. Notably, we discovered that protein arginine methyltransferase 5 (PRMT5) inhibitors markedly promote ferroptosis in RCC cells. Inhibition or knockdown of PRMT5 in RCC cell lines enhanced lipid peroxidation and reduced cell viability. PRMT5 interacted with and catalyzed the symmetric dimethylation of ACSL4 at the arginine 549 (R549) site, facilitating its degradation via the proteasome. In vivo, the combination of a PRMT5 inhibitor with anti-PD-1 therapy notably increased ferroptosis and reduced tumor growth. Furthermore, elevated PRMT5 levels were associated with unfavorable clinical outcomes in patients with renal cancer. Overall, our findings suggest that PRMT5 regulates ferroptosis in RCC by methylating ACSL4 at the R549 site, and its inhibition enhances the therapeutic efficacy of immunotherapy through the induction of ferroptosis.

The FOX transcription factor family plays a pivotal role in the malignant progression of tumors. We propose a hypothesis that FOXQ1 recruits p300 and BRD4 to super-enhancer regions. Our findings indicate that p300 acetylates Lys190 of FOXQ1, resulting in its recognition and binding by BRD4. Subsequently, BRD4 recruits RNA-Pol II to form a “FOXQ1-p300-BRD4-RNA Pol II” complex, which then binds to the super-enhancers of target genes. Meanwhile, acetylation at Lys190 of FOXQ1 directly enhances its binding affinity to super-enhancers. Consequently, more target oncogenes can be transcribed to promote CRC proliferation and metastasis. Our results suggest that FOXQ1 acts as a key regulator of super-enhancers, providing insights into its role in CRC and highlighting its potential as a therapeutic target.

Glioma is the most common primary tumor in the central nervous system, with glioblastoma (GBM) representing one of the most malignant forms, accounting for 46.1% of cases. GBM is characterized by rapid progression, high malignancy, and poor prognosis, with median survival remaining less than 15 months despite combined surgery, radiotherapy, and chemotherapy. NAT10, the only known acetyltransferase mediating N4-acetylcytidine (ac4C) modification in eukaryotes, has been implicated in promoting tumorigenesis and progression in colon cancer, bladder cancer, pancreatic ductal cancer, among others. In this study, we found that NAT10 is highly expressed in GBM and is positively correlated with malignant pathological features and poor prognosis in patients. In vitro experiments demonstrated that NAT10 promotes tumor proliferation, migration, and invasion. In vivo experiments further confirmed that NAT10 facilitates malignant progression of tumors. Mechanistically, we revealed that NAT10 regulates PIK3R2 stabilization through ac4C modification, thereby participating malignant characterization of GBM. Additionally, our data demonstrated a positive correlation between NAT10 and PIK3R2 in glioma patients. Taken together, our findings strongly suggest that NAT10 is a potential therapeutic target for GBM.

Background: Due to the low efficacy rates, effective biomarkers are desperately needed to determine populations of advanced esophageal squamous cell carcinoma (ESCC) that may benefit from immune checkpoint inhibitor (ICI) treatment.Objectives: To explore the relationship between IL-6 and the esophageal cancer tumor immune microenvironment using online databases and esophageal cancer tissue microarrays and to investigate the predictive role of IL-6 for immunotherapy in esophageal squamous carcinoma patients through clinical study data.Methods: RNA-seq datasets of ESCC patients were obtained from TCGA, and the relationship between IL-6 and immune cells was discovered using TIMER 2.0 databases. CD8, IL-6, and PD-L1 expression in ESCC tissue microarrays were measured using immunohistochemistry, and then the tumor microenvironment was classified. Furthermore, blood specimens were collected from advanced ESCC patients before they received PD-1 inhibitors, and follow-up was conducted to gather clinical survival data. Based on IL-6 levels. We divided the population into the high and low IL-6 groups, comparing the efficacy and survival of the two groups.Results: IL-6 positively correlated with mRNA levels of PD-L1, negatively correlated with immune cells, and positively correlated with immunosuppressive cells. High IL-6 expression in tissues might make PD-1/L1 blockade therapy less effective. Individuals with higher baseline plasma IL-6 levels had significantly lower objective remission rates and inferior PFS and OS. Elevated baseline IL-6 was demonstrated to be an independent risk factor for the prognosis of advanced ESCC patients using PD-1 inhibitors, according to COX regression analysis.Conclusion: IL-6 overexpression correlates with the immunosuppressive tumor microenvironment in ESCC, and it can be a predictive biomarker in ESCC patients received with PD-1 inhibitors.