Background: cyclic AMP response element-binding protein (CREB) mediates energy homeostasis and promotes stress resistance in non-cancerous tissues, which is similarto active reprogramming systems of cancer that enable adaptation and survival under environmental metabolic stress. This study was conducted to characterize the role of CREB in cancer cells in response to glucose starvation and investigate differentially expressed genes under glucose deprivation conditions. Methods: Several human cancer cell lines were used in this study. Transient transfection with siRNA, proliferation assays, and cell viability assays under normal culture conditions or glucose deprivation conditions were performed to explore the metabolic phenotype of CREB. To investigate cell death mode, assessment of poly(ADP-ribose) polymerase (PARP) cleavage by Western blot and an apoptosis assay using a fi ow cytometer were performed. And the CREB-specifi c gene expression signature under glucose deprivation conditions was investigated by microarray experiments and gene set enrichment analysis. Results: Expression of phosphorylated CREB was increased under glucose-free media conditions. Proliferation of CREB-knockdown cells was significantly suppressed compared with that of control cells under normal media conditions. The viability of CREB-knockdown cells was signifi cantly higher than that of control ones under metabolic stress conditions. Western blot analysis revealed that PARP cleavage induced by glucose deprivation was attenuated by knockdown of CREB. Apoptotic assay revealed that the number of cells undergoing apoptotic death decreased in response to knockdown of CREB under glucose deprivation conditions. CREB-specifi c gene expression signatures under glucose deprivation conditions revealed that energy metabolism-related gene sets such as glycolysis/gluconeogenesis, oxidative phosphorylation, and ATPsynthesis were highly enriched. Conclusions: CREB is essential for cellular proliferation under normal culture media conditions. Under glucose starvation conditions, CREB is activated and mediates apoptotic cell death in correlation with expression of energy metabolism-related gene sets.