Bromodomain and extraterminal domain proteins, especially bromodomain‑containing protein 4 (Brd4), have recently emerged as therapeutic targets for several cancers, although the role and mechanism of Brd4 in glioblastoma multiforme (GBM) are unclear. In this study, we aimed to explore the underlying mechanisms of the anti‑tumor effects of Brd4 and the bromodomain inhibitor JQ1 on glioma stem cells (GSCs). In vitro, JQ1 and small interfering RNAs targeting Brd4 (siBrd4) inhibited the proliferation and self‑renewal of GSCs. In vivo, JQ1 significantly inhibited the growth of xenograft GSCs tumors. The RNA‑seq analysis revealed that the PI3K‑AKT pathway played an important role in GBM. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 phosphorylation was downregulated by exposure to JQ1 in GSCs, thereby reducing PI3K and AKT activity. In addition, treatment with JQ1 inhibited MMP expression, thereby inhibiting degradation of the extracellular matrix by MMP and angiogenesis in GBM tumors. Suppression of AKT phosphorylation inhibited the expression of the retinoblastoma/E2F1 complex, resulting in cell cycle arrest. In addition, treatment with siBrd4 or JQ1 induced apoptosis by activating AKT downstream target genes involved in apoptosis. In conclusion, these results suggest that Brd4 has great potential as a therapeutic target, and JQ1 has notable anti‑tumor effects against GBM which may be mediated via the VEGF/PI3K/AKT signaling pathway.

Purpose: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the clinic all over the world, which has become a public health challenge. The T/N/M staging system plays a core role in HCC prognosis. However, it cannot precisely stratify the risk of HCC prognosis. MiR-454-3p plays an important role in the progression of tumors. Therefore, we need to develop more reliable prognostic markers for HCC patients which can focus on miR-454-3p. Methods: We used Chi-square and Fisher exact tests to assess correlations between miR-454-3p expression and clinical parameters in liver cancer patients from The Cancer Genome Atlas database (TCGA). Then, Cox regression analysis, Kaplan-Meier curve, and log-rank test were used to compare the difference of survival between the high-expression group and low-expression group, and P value was included. Finally, we used TCGA data set to carry out gene enrichment analysis. Results: In this research, the expression of miR-454-3p increased in HCC and was associated with patient survival, G3/G4 staging, III/IV staging and T staging. Higher miR-454-3p expressed patients had shorter survival time. Besides, mitotic spindle, G2M checkpoint, and E2F targets were differentially enriched in miR-454-3p high-expression phenotype by Gene set enrichment analysis. Conclusion: Overexpression of miR-454-3p may be a significant and independent predictor of poor prognosis in HCC patients.

Pyruvate dehydrogenase kinase 1 (PDK1) is a key factor in the connection between glycolysis and the tricarboxylic acid cycle. Restoring the mitochondrial OXPHOS function by inhibiting glycolysis through targeting PDK1 has become a hot spot for tumor therapy. However, the specific mechanism by which metabolic changes affect mitochondrial function remains unclear. Recent studies have found that mitochondrial quality control such as mitochondrial protein homeostasis plays an important role in maintaining mitochondrial function. Here, we focused on PDK1 and explored the specific mechanism by which metabolic changes affect mitochondrial OXPHOS function. We showed that glucose metabolism in HepG2 and HepG3B cells switched from anaerobic glycolysis to the mitochondrial tricarboxylic acid cycle under different concentrations of dichloroacetate (DCA) or short hairpin PDK1. After DCA treatment or knockdown of PDK1, the mitochondrial morphology was gradually condensed and exhibited shorter and more fragmented filaments. Additionally, expression of the mitochondrial autophagy proteins parkin and PTEN-induced kinase was down-regulated, and the biosynthetic protein peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) and its regulated complex I, III, IV, and V protein were down-regulated. This indicated that PDK1 inhibition affected the level of mitochondrial quality control. Analysis of mitochondrial function revealed significantly increased mitochondrial reactive oxygen species and decreased membrane potential. Therefore, glucose metabolism reprogramming by PDK1 inhibition could induce mitochondrial quality control disorders to aggravate mitochondrial stress damage.