CREB acts as a common transcription factor for major epigenetic repressors; DNMT3B, EZH2, CUL4B and E2F6

Abstract

CREB signaling is known for several decades, but how it regulates both positive and negative regulators of cell proliferation is not well understood. On the other hand functions of major epigenetic repressors such as DNMT3B, EZH2 and CUL4B for their repressive epigenetic modifications on chromatin have also been well studied. However, there is very limited information available on how these repressors are regulated at their transcriptional level. Here, using computational tools and molecular techniques including site directed mutagenesis, promoter reporter assay, chromatin immunoprecipitation (ChIP), we identified that CREB acts as a common transcription factor for DNMT3B, EZH2, CUL4B and E2F6. ChIP assay revealed that pCREB binds to promoters of these repressors at CREs and induce their transcription. As expected, the expression of these repressors and their associated repressive marks particularly H3K27me3 and H2AK119ub are increased and decreased upon CREB overexpression and knock-down conditions respectively in the cancer cells indicating that CREB regulates the functions of these repressors by activating their transcription. Since CREB and these epigenetic repressors are overexpressed in various cancer types, our findings showed the molecular relationship between them and indicate that CREB is an important therapeutic target for cancer therapy.

Keywords: CRE; CREB; CUL4B; DNMT3B; E2F6; EZH2; cAMP responsive element.