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Glioblastoma (GBM) is the deadliest primary brain tumor that is highly resistant to current treatments. Polo-like kinase 1 (PLK1) and signal transducer and activator of transcription 3 (STAT3) are highly expressed in gliomas, especially GBM. Previous studies have shown reciprocal activation between PLK1 and STAT3 and that they regulate the same pools of MYC downstream. We have demonstrated that PLK1 and STAT3 levels are elevated in gliomas compared with those in normal brain tissues, and high expression of both PLK1 and STAT3 is associated with poor prognosis in TCGA. Moreover, there was direct or indirect reciprocal regulation between PLK1 and STAT3. Furthermore, we found that PLK1 and STAT3 can regulate the same pools of MYC downstream. Compared to monotherapy, combined treatment of glioma cells with PLK1 and STAT3 inhibitors, BI2536 and Stattic, respectively, showed lower expression of MYC, synergistic induction of cell invasion and apoptosis in vitro, and tumor inhibition in xenografts. PLK1 and STAT3 were able to directly regulate the expression of MYC and induce apoptosis of glioma cells through the regulation of MYC. These findings may help develop a therapeutic strategy for dual inhibition of PLK1 and STAT3 against the tumorigenesis of glioma.

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., 1. We evaluated BRD4, not BRD2 or BRD3, has value in targeted glioma therapy. 2. A signaling pathway involving BRD4 and Notch1 sustains GICs’ self‐renewal. 3. BRD4 was enriched at Notch1 promoter region and may be involved in the process of tumor metabolism. 4. BRD4 abolished the tumorigenicity of GICs in intracranial model after I‐BET151 (BET inhibitor) treatment.