GSK-3α Is a Novel Target of CREB and CREB-GSK-3α Signaling Participates in Cell Viability in Lung Cancer

Overexpression or activation of cyclic AMP-response element-binding protein (CREB) has been known to be involved in several human malignancies, including lung cancer. Genes regulated by CREB have been reported to suppress apoptosis, induce cell proliferation, inflammation, and tumor metastasis. However, the critical target genes of CREB in lung cancer have not been well understood. Here, we identified GSK-3 alpha as one of the CREB target genes which is critical for the viability of lung cancer cells. The CREB knockdown significantly reduced the expression of GSK-3 alpha and the direct binding of CREB on the promoter of GSK3A was identified. Kaplan-Meier analysis with a public database showed a prognostic significance of aberrant GSK-3 alpha expression in lung cancer. Inhibition of GSK-3 alpha suppressed cell viability, colony formation, and tumor growth. For the first time, we demonstrated that GSK-3 alpha is regulated by CREB in lung cancer and is required for the cell viability. These findings implicate CREB-GSK-3 alpha axis as a novel therapeutic target for lung cancer treatment.