Article

Methyl-H3K9-binding protein MPP8 mediates E-cadherin gene silencing and promotes tumour cell motility and invasion.

Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
The EMBO Journal (impact factor: 9.2). 11/2010; 29(21):3673-87. DOI:10.1038/emboj.2010.239 pp.3673-87
Source: PubMed

ABSTRACT H3K9 methylation has been linked to a variety of biological processes including position-effect variegation, heterochromatin formation and transcriptional regulation. To further understand the function of H3K9 methylation, we have identified and characterized MPP8 as a methyl-H3K9-binding protein. MPP8 displays an elevated expression pattern in various human carcinoma cells, whereas knocking-down MPP8 results in the loss of cellular mesenchymal marker as well as the reduction of tumour cell migration and invasiveness, suggesting that MPP8 contributes to tumour progression. Following characterization demonstrates that MPP8 targets the E-cadherin gene promoter and modulates the expression of this key regulator of cell behaviour and tumour progression through its methyl-H3K9 binding. Furthermore, MPP8 interacts with H3K9 methyltransferases GLP and ESET, as well as DNA methyltransferase 3A. MPP8 knockdown decreases DNA methylation on E-cadherin CpG island attended by the loss of DNMT3A localization, indicating MPP8 also directs DNA methylation. Together, our results suggest a model by which MPP8 recognizes methyl-H3K9 marks and directs DNA methylation to repress tumour suppressor gene expression and, in turn, has an important function in epithelial-to-mesenchymal transition and metastasis.

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Keywords

cellular mesenchymal marker
 
DNA methyltransferase 3A
 
DNMT3A localization
 
E-cadherin CpG island
 
E-cadherin gene promoter
 
elevated expression pattern
 
epithelial-to-mesenchymal transition
 
H3K9 methyltransferases GLP
 
key regulator
 
knocking-down MPP8 results
 
methyl-H3K9 binding
 
methyl-H3K9-binding protein
 
MPP8 contributes
 
MPP8 interacts
 
position-effect variegation
 
repress tumour suppressor gene expression
 
transcriptional regulation
 
tumour cell migration
 
tumour progression
 
various human carcinoma cells