Methyl-H3K9-binding protein MPP8 mediates E-cadherin gene silencing and promotes tumour cell motility and invasion.
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.
Kokura
Kenji
K
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Sun
Lidong
L
Bedford
Mark T
MT
Fang
Jia
J
D000595:Amino Acid Sequence; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D015820:Cadherins / Q000235:genetics*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic
D014408:Biomarkers, Tumor; D015820:Cadherins; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C547278:MPHOSPH8 protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A