Glioma is one of the most primary malignant brain tumors, and glioblastoma multiform (GBM) is the most common and highly aggressive glioma. Most GBM are high malignant, poor prognosis, resistant to conventional therapy, and prone to recurrence. Therefore, it is crucial to explore novel therapeutics strategies for the treatment and prognosis of GBM. In this study, we elucidated that the maximal overexpression of DNA-directed RNA polymerase II subunit J-1 (POLR2J) was observed in GBM compared with normal tissues among all cancer types, and high expression of POLR2J or its co-expressed genes predicted poor outcome of GBM patients. DNA replication were significantly enriched in the GBM clinical samples with high POLR2J expression, and POLR2J suppression inhibited the proliferation and triggered cell cycle G1/G0 phase arrest of GBM cells. HDAC inhibitors, such as vorinostat, are identified as effective agents against GBM. We showed that POLR2J silence activated UPR and significantly enhanced anti-GBM activity of vorinostat via suppressing cell proliferation and inducing apoptosis. In addition, POLR2J promoted epithelial-mesenchymal transition (EMT) and the metastatic potentials of GBM cells. Furthermore, POLR2J expression was negatively relevant to the number of B cells, neutrophil, myeloid dendritic cells, CD4 + T cells and etc. Meanwhile, the expression of POLR2J was negatively correlative to the expression of immunotherapy-related genes. Our study confirmed a novel oncogene POLR2J in GBM progression as well as provided a promising strategy for the chemotherapy and immunotherapy of GBM treatment.

Gastric cancer is the third leading cause of cancer related death worldwide. Due to the complexity and heterogeneity of gastric cancer, the development of targeted drugs is somehow limited, but is urgently needed. Since the expression of Bruton tyrosine kinase (BTK) was significantly associated with the prognosis of gastric cancer patients, we aimed to determine the anti-cancer activity of HZ-A-018, which was a novel derivative of ACP-196, in gastric cancer cells. As a result, HZ-A-018 presented a stronger anti-proliferation activity than ACP-196 via the substantial suppression of AKT/S6 pathway. In addition, HZ-A-018, but not ACP-196, exerted the synergistic effects in combined treatment with 5-FU both in vitro and in vivo, without exacerbating the adverse effects of 5-FU. Mechanismly, the combination of HZ-A-018 and 5-FU remarkably reduced the expression of RRM2, which played an essential role in proliferation and drug sensitivity in gastric cancer cells. In summary, our work demonstrated the stronger anti-cancer activity of HZ-A-018 than ACP-196 in gastric cancer cells, and revealed synergistic effects of HZ-A-018 and 5-FU combination probably through the inhibition of RRM2 via AKT/S6 pathway, thereby providing a promising therapeutic strategy in gastric cancer.