Abstract
The transmembrane adaptor protein Cbp (or PAG1) functions as a suppressor of Src-mediated tumor progression by promoting the inactivation of Src. The expression of Cbp is down-regulated in Src-transformed cells and in various human cancer cells, suggesting a potential role for Cbp as a tumor suppressor. However, the mechanisms underlying the down-regulation of Cbp remain unknown. The present study shows that Cbp expression is down-regulated by epigenetic histone modifications via the MAPK/PI3K pathway. In mouse embryonic fibroblasts, transformation by oncogenic Src and Ras induced a marked down-regulation of Cbp expression. The levels of Cbp expression were inversely correlated with the activity of MEK and Akt, and Cbp down-regulation was suppressed by inhibiting MEK and PI3K. Src transformation did not affect the stability of Cbp mRNA, the transcriptional activity of the cbp promoter, or the DNA methylation status of the cbp promoter CpG islands. However, Cbp expression was restored by treatment with histone deacetylase (HDAC) inhibitors and by siRNA-mediated knockdown of HDAC1/2. Src transformation significantly decreased the acetylation levels of histone H4 and increased the trimethylation levels of histone H3 lysine 27 in the cbp promoter. EGF-induced Cbp down-regulation was also suppressed by inhibiting MEK and HDAC. Furthermore, the inhibition of MEK or HDAC restored Cbp expression in human cancer cells harboring Cbp down-regulation through promoter hypomethylation. These findings suggest that Cbp down-regulation is primarily mediated by epigenetic histone modifications via oncogenic MAPK/PI3K pathways in a subset of cancer cells.
Highlights
Cbp (Csk-binding protein),2 known as PAG1, is a transmembrane adaptor protein composed of a short extracellular domain and a longer cytoplasmic domain [1, 2]
Mic domain of Cbp contains palmitoylation sites that are required for localization to a cholesterol-enriched membrane microdomain and multiple tyrosine residues that can be phosphorylated by Src family kinases (SFKs)
We previously reported that Cbp expression is markedly down-regulated by Src-mediated cell transformation and in some human cancer cells, and that the re-expression of Cbp efficiently suppresses Src transformation and tumorigenesis [11]
Summary
Cbp (Csk-binding protein),2 known as PAG1, is a transmembrane adaptor protein composed of a short extracellular domain and a longer cytoplasmic domain [1, 2]. The present study shows that Cbp is down-regulated by an epigenetic mechanism involving the deacetylation/methylation of histones, but not DNA methylation, in the cbp promoter via the activation of MAPK/PI3K pathways.
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