Abstract
The tumour-suppressor gene CDKN1A (encoding p21Waf/Cip1) is thought to be epigenetically repressed in cancer cells. FBI-1 (ZBTB7A) is a proto-oncogenic transcription factor repressing the alternative reading frame and p21WAF/CDKN1A genes of the p53 pathway. FBI-1 interacts directly with MBD3 (methyl-CpG–binding domain protein 3) in the nucleus. We demonstrated that FBI-1 binds both non-methylated and methylated DNA and that MBD3 is recruited to the CDKN1A promoter through its interaction with FBI-1, where it enhances transcriptional repression by FBI-1. FBI-1 also interacts with the co-repressors nuclear receptor corepressor (NCoR), silencing mediator for retinoid and thyroid receptors (SMRT) and BCL-6 corepressor (BCoR) to repress transcription. MBD3 regulates a molecular interaction between the co-repressor and FBI-1. MBD3 decreases the interaction between FBI-1 and NCoR/SMRT but increases the interaction between FBI-1 and BCoR. Because MBD3 is a subunit of the Mi-2 autoantigen (Mi-2)/nucleosome remodelling and histone deacetylase (NuRD)-HDAC complex, FBI-1 recruits the Mi-2/NuRD-HDAC complex via MBD3. BCoR interacts with the Mi-2/NuRD-HDAC complex, DNMTs and HP1. MBD3 and BCoR play a significant role in the recruitment of the Mi-2/NuRD-HDAC complex– and the NuRD complex–associated proteins, DNMTs and HP. By recruiting DNMTs and HP1, Mi-2/NuRD-HDAC complex appears to play key roles in epigenetic repression of CDKN1A by DNA methylation.
Highlights
Factor that binds to the inducer of short transcripts of human immunodeficiency virus-1 (FBI-1) (ZBTB7A) is a recently characterized proto-oncoprotein of the POZdomain Kruppel-like (POK) family of transcription factors
We have demonstrated that expression of the fatty acid synthase (FASN), which is important in palmitate synthesis and cell proliferation in cancer cells, is potently activated by FBI-1 in the presence of sterol regulatory element binding protein-1 (SREBP-1) [4]
Because interaction with the transcription co-repressor complex changes the modifications of chromatin, we investigated the changes in epigenetic histone marks by FBI-1, MBD3 and BCL6 corepressor (BCoR) recruited to the proximal promoter of CDKN1A
Summary
Factor that binds to the inducer of short transcripts of human immunodeficiency virus-1 (FBI-1) (ZBTB7A) is a recently characterized proto-oncoprotein of the POZdomain Kruppel-like (POK) family of transcription factors. It plays important roles in the cell cycle, cell differentiation, proliferation, fatty acid synthesis, immune responses and oncogenesis. We have demonstrated that expression of the fatty acid synthase (FASN), which is important in palmitate synthesis and cell proliferation in cancer cells, is potently activated by FBI-1 in the presence of sterol regulatory element binding protein-1 (SREBP-1) [4].
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