CBX7 reprograms metabolic flux to protect against meningioma progression by modulating the USP44/c-MYC/LDHA axis.

Meningioma is one of the most common primary neoplasms in the central nervous system, whereas there is still no specific molecularly targeted therapy that has been approved for the clinical treatment of aggressive meningiomas. There is therefore an urgent demand to decrypt the biological and molecular landscape of malignant meningioma. Here, through the in-silica prescreening and 10-year follow-up of 445 meningioma patients, we uncovered that CBX7 is progressively decreased with malignancy grade and neoplasia stage in meningioma and a high CBX7 expression level predicts a favorable prognosis in meningioma patients. CBX7 restoration significantly induces cell cycle arrest and inhibits meningioma cell proliferation. iTRAQ-based proteomics analysis indicated that CBX7 restoration triggers the metabolic shift from glycolysis to oxidative phosphorylation. The mechanistic study demonstrated that CBX7 promotes the proteasome-dependent degradation of c-MYC proteins by transcriptionally inhibiting the expression of a c-MYC deubiquitinase, USP44, which attenuates c-MYC-mediated transactivation of LDHA transcripts and further inhibits glycolysis and subsequent cellular proliferation. More importantly, the functional role of CBX7 was further confirmed in both subcutaneous and orthotopic meningioma xenografts mouse models and human meningioma patients. Together, our results shed light on the critical role of CBX7 during meningioma malignancy progression and identified the CBX7/USP44/c-MYC/LDHA axis as a promising therapeutic target against meningioma progression.

Identification of the Key Immune Cells and Genes for the Diagnostics and Therapeutics of Meningioma.

BACKGROUND: Dysregulation of immune infiltration critically contributes to the tumorigenesis and progression of meningiomas. However, the landscape of immune microenvironment and key genes correlated with immune cell infiltration remains unclear. METHODS: Four Gene Expression Omnibus data sets were included. CIBERSORT algorithm was utilized to analyze the immune cell infiltration in samples. Wilcoxon test, Random Forest algorithm, and Least Absolute Shrinkage and Selection Operator regression were adopted in identifying significantly different infiltrating immune cells and differentially expressed genes (DEGs). Functional enrichment analysis was performed by Kyoto Encyclopedia of Genes and Genomes and Gene Ontology. The correlation between genes and immune cells was evaluated via Spearman's correlation analysis. Receiver Operator Characteristic curve analysis evaluated the markers' diagnostic effectiveness. The mRNA-miRNA and Drug-Gene-Immune cell interaction networks were constructed to identify potential diagnostic and therapeutic targets. RESULTS: Plasma cells, M1 macrophages, M2 macrophages, neutrophils, eosinophils, and activated NK cells were the significantly different infiltrating immune cells in meningioma. A total of 951 DEGs, associated with synaptic function and structure, ion transport regulation, brain function, and immune-related pathways, were identified. Among 11 hub DEGs, RYR2 and TTR were correlated with plasma cells; SNCG was associated with NK cells; ADCY1 exhibited excellent diagnostic effectiveness; and ADCY1, BMX, KCNA5, SLCO4A1, and TTR could be considered as therapeutic targets. CONCLUSIONS: ADCY1 can be identified as a diagnostic marker; ADCY1, BMX, KCNA5, SLCO4A1, and TTR are potential therapeutic targets, and their associations with macrophages, neutrophils, NK cells, and plasma cells might impact the tumorigenesis of meningiomas.

ITF2357 induces cell cycle arrest and apoptosis of meningioma cells via the PI3K-Akt pathway.

As a type of central nervous system tumor, meningioma usually compresses the nerve center due to its local expansion, further causing neurological deficits. However, there are limited therapeutic approaches for meningiomas. ITF2357, a potent class I and II histone deacetylase inhibitor (HDACi), has been shown to inhibit cell proliferation, promote apoptosis, and block the cell cycle in various sarcoma cells, including glioblastoma and peripheral T-cell lymphoma. Here, we investigated the potential role of ITF2357 on meningioma cancer cells (IOMM-Lee cells). First, we demonstrated that the half-maximal inhibitory concentration (IC50) of ITF2357 was 1.842 µM by MTT assay. In addition, ITF2357 effectively inhibited the proliferation and colonization ability of IOMM-Lee cells. Flow cytometry analysis showed that ITF2357 induced G0/G1 and G2/M phase cell cycle arrest and cell apoptosis. Mechanically, the RNA sequencing data revealed that ITF2357 could affect the PI3K-Akt signaling pathway and the cell cycle progression. Furthermore, the expression levels of Akt, PI3K, p-Akt, and p-PI3K were determined by western blotting. Collectively, our data revealed that ITF2357 induces G0 G1 and G2/M phase arrest and apoptosis by inhibiting hyperactivation of the PI3K-Akt pathway, ultimately inhibiting cell viability and proliferation of meningioma cells, which developed a new approach to the treatment of meningioma.

Disulfiram-loaded hollow copper sulfide nanoparticles show anti-tumor effects in preclinical models of colorectal cancer.

Colorectal cancer is one of the most common malignancies causing the majority of cancer-related deaths. There is an urgent need to develop new anticancer modalities. Recently, efforts have been made to turn clinically approved drugs into anticancer agents in specific tumor microenvironments via NPs. Disulfiram (DSF) as an effective copper (Cu2+)-dependent anti-tumour drug, which has been more widely used in antitumor research. Here, we constructed a novel therapeutic nanoplatforms, DSF@CuS, by encapsulating DSF in hollow CuS NPs to enable in situ chemoselective activation of DSF and hyperthermal amplified chemotherapy. The anticancer effect of DSF was enhanced by the thermal energy generated under NIR irradiation through the intrinsic photothermal conversion of CuS. As a result, significant apoptosis was induced in vitro, and tumor elimination was achieved in vivo. Collectively, DSF@CuS combined with photothermal therapy can significantly promote the apoptosis of CT26 colorectal cancer cells both in vitro and in vivo, providing a potential theoretical agent for the treatment of colorectal cancer.

Construction Of High Loading Natural Active Substances Nanoplatform and Application in Synergistic Tumor Therapy.

Background: Natural bioactive substances have been widely studied for their superior anti-tumor activity and low toxicity. However, natural bioactive substances suffer from poor water-solubility and poor stability in the physiological environment. Therefore, to overcome the drawbacks of natural bioactive substances in tumor therapy, there is an urgent need for an ideal nanocarrier to achieve high bioactive substance loading with low toxicity. Materials and Methods: Face-centered cubic hollow mesoporous Prussian Blue (HMPB) NPs were prepared by stepwise hydrothermal method. Among them, PVP served as a protective agent and HCl served as an etching agent. Firstly, MPB NPs were obtained by 0.01 M HCl etching. Then, the highly uniform dispersed HMPB NPs were obtained by further etching with 1 M HCl. Results: In this work, we report a pH-responsive therapeutic nanoplatform based on HMPB NPs. Surprisingly, as-prepared HMPB NPs with ultra-high bioactive substances loading capacity of 329 µg mg-1 owing to the large surface area (131.67 m2 g-1) and wide internal pore size distribution (1.8-96.2 nm). Moreover, with the outstanding photothermal conversion efficiency of HMPB NPs (30.13%), natural bioactive substances were released in the tumor microenvironment (TME). HMPB@PC B2 achieved excellent synergistic therapeutic effects of photothermal therapy (PTT) and chemotherapy (CT) in vivo and in vitro without causing any extraneous side effects. Conclusion: A biocompatible HMPB@PC B2 nanoplatform was constructed by simple physical adsorption. The in vitro and in vivo experiment results demonstrated that the synergy of PTT/CT provided excellent therapeutic efficiency for cervical cancer without toxicity. Altogether, as-designed nanomedicines based on natural bioactive substances may be provide a promising strategy for cancer therapy.

Critical regulation of a NDIME/MEF2C axis in embryonic stem cell neural differentiation and autism.

A microdeletion within human chromosome 5q14.3 has been associated with the occurrence of neurodevelopmental disorders, such as autism and intellectual disability, and MEF2C haploinsufficiency was identified as main cause. Here, we report that a brain-enriched long non-coding RNA, NDIME, is located near the MEF2C locus and is required for normal neural differentiation of mouse embryonic stem cells (mESCs). NDIME interacts with EZH2, the major component of polycomb repressive complex 2 (PRC2), and blocks EZH2-mediated trimethylation of histone H3 lysine 27 (H3K27me3) at the Mef2c promoter, promoting MEF2C transcription. Moreover, the expression levels of both NDIME and MEF2C were strongly downregulated in the hippocampus of a mouse model of autism, and the adeno-associated virus (AAV)-mediated expression of NDIME in the hippocampus of these mice significantly increased MEF2C expression and ameliorated autism-like behaviors. The results of this study reveal an epigenetic mechanism by which NDIME regulates MEF2C transcription and neural differentiation and suggest potential effects and therapeutic approaches of the NDIME/MEF2C axis in autism.

Sin3a-Tet1 interaction activates gene transcription and is required for embryonic stem cell pluripotency.

Sin3a is a core component of histone-deacetylation-activity-associated transcriptional repressor complex, playing important roles in early embryo development. Here, we reported that down-regulation of Sin3a led to the loss of embryonic stem cell (ESC) self-renewal and skewed differentiation into mesendoderm lineage. We found that Sin3a functioned as a transcriptional coactivator of the critical Nodal antagonist Lefty1 through interacting with Tet1 to de-methylate the Lefty1 promoter. Further studies showed that two amino acid residues (Phe147, Phe182) in the PAH1 domain of Sin3a are essential for Sin3a-Tet1 interaction and its activity in regulating pluripotency. Furthermore, genome-wide analyses of Sin3a, Tet1 and Pol II ChIP-seq and of 5mC MeDIP-seq revealed that Sin3a acted with Tet1 to facilitate the transcription of a set of their co-target genes. These results link Sin3a to epigenetic DNA modifications in transcriptional activation and have implications for understanding mechanisms underlying versatile functions of Sin3a in mouse ESCs.

Dysregulation of the SIRT1/OCT6 Axis Contributes to Environmental Stress-Induced Neural Induction Defects.

Environmental stresses are increasingly acknowledged as core causes of abnormal neural induction leading to neural tube defects (NTDs). However, the mechanism responsible for environmental stress-triggered neural induction defects remains unknown. Here, we report that a spectrum of environmental stresses, including oxidative stress, starvation, and DNA damage, profoundly activate SIRT1, an NAD+-dependent lysine deacetylase. Both mouse embryos and in vitro differentiated embryonic stem cells (ESCs) demonstrated a negative correlation between the expression of SIRT1 and that of OCT6, a key neural fate inducer. Activated SIRT1 radically deacetylates OCT6, triggers an OCT6 ubiquitination/degradation cascade, and consequently increases the incidence of NTD-like phenotypes in mice or hinders neural induction in both human and mouse ESCs. Together, our results suggest that early exposure to environmental stresses results in the dysregulation of the SIRT1/OCT6 axis and increases the risk of NTDs.