Bromodomain and extraterminal domain (BET) family proteins are considered to be epigenetic readers that regulate gene expression by recognizing acetyl lysine residues on histones and nonhistone chromatin factors and have been classified as curative targets for a variety of cancers. Glioma-initiating cells (GICs), which commit self-renewal, perpetual proliferation, multidirectional differentiation, and vigorous tumorigenicity, sustain the peculiar genetic and epigenetic diversification in the GBM patients, thus, GICs result in tumor recurrence. Abundant evidence demonstrates that BET proteins regulate differentiation of stem cells. However, it endures ambiguous how individual BET proteins take part in GIC advancement, and how do small molecule inhibitors like I-BET151 target functional autonomous BET proteins. Here, we validated that BRD4, not BRD2 or BRD3, has value in targeted glioma therapy. We announce a signaling pathway concerning BRD4 and Notch1 that sustains the self-renewal of GICs. Moreover, in-depth mechanistic research showed that BRD4 was concentrated at the promoter region of Notch1 and may be involved in the process of tumor metabolism. Furthermore, in intracranial models, I-BET151 eliminated U87 GICs' tumorigenicity. The outcomes of this research could be conducive to design clinical trials for treatment of glioma based on BRD4.
Glioblastoma multiforme (GBM) is an intracranial tumor; the feature is higher malignant and poorer prognosis. The search for therapeutic targets for gliomas has always been a focus of research in the field of neurology. The unusual expression of epithelial membrane protein 1 (EMP1) has been proved in most tumors. In our study, we determined the expression level of EMP1 expression in glioma tissues. There were higher levels of EMP1 in glioma tissues—particularly GBM tissues—than those in normal brain tissues. Then we discovered that silencing EMP1 inhibited glioma cell invasion and proliferation through inhibiting the PI3K‐AKT signaling pathway. Subsequently, we investigated the function of EMP1 on glioma stem cells and found that it regulates the expression of CD44 in such cells to promote stemness. Taken together, the new strategies for the treatment of glioma may be provided by these finding, thereby improving the prognosis associated with it.
Glioma is the most common adult malignant primary brain tumor; however, the effect of chemotherapy is often limited by drug-resistance and poor prognosis is common. Ring finger protein 138 (RNF138) belongs to the E3 ligase family, and has significantly higher expression level in glioma tissue than in noncancerous brain tissues. Epithelial-mesenchymal-transition (EMT) has a critical role in cancer invasion and metastasis, ultimately leading to increased cell motility and resistance to genotoxic agents. Extracellular-signal regulated kinase (Erk) pathways promote the growth of glioma cells and enhance tumor invasion, with a role in the progression of EMT. However, the association between RNF138 and human glioma progression remains poorly understood. Relatively little is known about the association between RNF138, Erk, and EMT in glioma progression. In the current study, experiments were performed to explore the potential roles and mechanisms of RNF138 in glioblastoma in vitro and in vivo. Glioma cell line proliferation, migration and invasion were inhibited by knockdown of RNF138 in vitro. By lowering the RNF138 expression, cleaved caspase3 and E-cadherin were upregulated, while phospho-Erk1/2, vimentin, MMP2, HIF-1α and VEGF were downregulated in U87 and U251 cells in vitro. In vivo findings revealed that the growth of U87 cell-transplanted tumors in nude mice was inhibited in tumors with RNF138 knockdown. These findings suggested that downregulation of RNF138 inhibited glioma cell proliferation, migration, and invasion, and reversed EMT, potentially via Erk signaling pathway. Therefore, RNF138 may be a potential therapeutic target against glioma.
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