Downregulation of CREB Promotes Cell Proliferation by Mediating G(1)/S Phase Transition in Hodgkin Lymphoma

The cyclic-AMP response element-binding protein (CREB), a well-known nuclear transcription factor, has been shown to play an essential role in many cellular processes, including differentiation, cell survival, and cell proliferation, by regulating the expression of downstream genes. Recently, increased expression of CREB was frequently found in various tumors, indicating that CREB is implicated in the process of tumorigenesis. However, the effects of CREB on Hodgkin lymphoma (HL) remain unknown. To clarify the role of CREB in HL, we performed knockdown experiments in HL. We found that downregulation of CREB by short hairpin RNA (shRNA) resulted in enhancement of cell proliferation and promotion of G(1)/S phase transition, and these effects can be rescued by expression of shRNA-resistant CREB. Meanwhile, the expression level of cell cycle-related proteins, such as cyclin D1, cyclin E1, cyclin-dependent kinase 2 (CDK2), and CDK4, was elevated in response to depletion of CREB. Furthermore, we performed chromatin immunoprecipitation (ChIP) assay and confirmed that CREB directly bound to the promoter regions of these genes, which consequently contributed to the regulation of cell cycle. Consistent with our results, a clinical database showed that high expression of CREB correlates with favorable prognosis in B-cell lymphoma patients, which is totally different from the function of CREB in other cancers such as colorectal cancer, acute myeloid leukemia, and some endocrine cancers. Taken together, all of these features of CREB in HL strongly support its role as a tumor suppressor gene that can decelerate cell proliferation by inhibiting the expression of several cell cycle-related genes. Our results provide new evidence for prognosis prediction of HL and a promising therapeutic strategy for HL patients.