Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase involved in cell proliferation, invasion, angiogenesis, and metastasis in various cancers, including hepatocellular carcinoma (HCC). However, the role and molecular mechanisms of EZH2 in HCC radiosensitivity remain unclear. Here, we show that EZH2 is upregulated in HCC cells and the aberrantly overexpressed EZH2 is associated with the poor prognosis of HCC patients. Using miRNA databases, we identified miR‐138‐5p as a regulator of EZH2. We also found that miR‐138‐5p was suppressed by EZH2‐induced H3K27me3 in HCC cell lines. MiR‐138‐5p overexpression and EZH2 knockdown enhanced cellular radiosensitivity while inhibiting cell migration, invasion, and epithelial‐mesenchymal transition (EMT). Analysis of RNA‐seq datasets revealed that the hypoxia‐inducible factor‐1 (HIF‐1) signaling pathway was the main enrichment pathway for differential genes after miR‐138‐5p overexpression or EZH2 knockdown. Expression level of HIF‐1α was significantly suppressed after miR‐138‐5p overexpression or silencing of EZH2. HIF‐1α silencing mitigated resistance of HCC cells and inhibited EMT. This study establishes the EZH2/miR‐138‐5p/HIF‐1α as a potential therapeutic target for sensitizing HCC to radiotherapy.

Objectives: Glioma is one of the most aggressive brain tumours with poor overall survival despite advanced technology in surgical resection, chemotherapy and radiation. Progression and recurrence are the hinge causes of low survival. Our aim is to explain the concrete mechanism in the proliferation and progression of tumours based on tumour microenvironment (TME). The main purpose is to illustrate the mechanism of proton pump inhibitors (PPIs) in affecting acidity, hypoxia, oxidative stress, inflammatory response and autophagy based on the TME to induce apoptosis and enhance the sensitivity of chemoradiotherapy.Findings: TME is the main medium for tumour growth and progression. Acidity, hypoxia, inflammatory response, autophagy, angiogenesis and so on are the main causes of tumour progress. PPIs, as a common clinical drug to inhibit gastric acid secretion, have the advantages of fast onset, long action time and small adverse reactions. Nowadays, several kinds of literature highlight the potential of PPIs in inhibiting tumour progression. However, long‐term use of PPIs alone also has obvious side effects. Therefore, till now, how to apply PPIs to promote the effect of radio‐chemotherapy and find the concrete dose and concentration of combined use are novel challenges.Conclusions: PPIs display the potential in enhancing the sensitivity of chemoradiotherapy to defend against glioma based on TME. In the clinic, it is also necessary to explore specific concentrations and dosages in synthetic applications.