BACKGROUND: Glioma is a type of tumor that occurs in the brain and accounts for almost 30 % of all brain and central nervous system tumors and 80 % of all malignant brain tumors. In this study, we investigate the role of cAMP response element-binding protein (CREB) in the progression of glioma. METHODS: Tissue samples from glioma patients were collected and examined for expression of CREB and its correlation with tumor grades. CREB was then knocked down via siRNA to see if reduced expression of CREB affects cell proliferation and migration. Factors involved in cell cycles, adhesion and apoptosis were examined as well. Moreover, CRESP/CAS9 mediated knockout of CREB was conducted and athymic Nude mice model was used to investigate CREB's role in vivo. RESULTS: The evaluated expression level of CREB in glioma patients was correlated with tumor grades. Knockdown of CREB via siRNA in glioma cell line U251 signifi cantly inhibited the proliferation and migration of tumor cells. Moreover, CyclinD1 and Bcl-2 expression were reduced, as well as phosphorylation of IRK1/2 and AKT. Additionally, knockout of CREB via CRESP/CAS9 inhibited tumor formation of U251 cells in athymic Nude mice model. CONCLUSIONS: In conclusion, our data suggest that over expression of CREB may contribute to progression of glioma and knockdown of CREB expression may serve as a novel target for therapy (Tab. 1, Fig. 6, Ref. 25).