Methyl-H3K9-binding Protein MPP8 Mediates E-cadherin Gene Silencing and Promotes Tumour Cell Motility and Invasion

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2010 Sep 28

PMID 20871592

Citations 78

Authors

Kenji Kokura

Lidong Sun

Mark T Bedford

Jia Fang

Affiliations

Soon will be listed here.

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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References

Bua D, Kuo A, Cheung P, Liu C, Migliori V, Espejo A . Epigenome microarray platform for proteome-wide dissection of chromatin-signaling networks. PLoS One. 2009; 4(8):e6789. PMC: 2777412. DOI: 10.1371/journal.pone.0006789. View

Peinado H, Olmeda D, Cano A . Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?. Nat Rev Cancer. 2007; 7(6):415-28. DOI: 10.1038/nrc2131. View

Herranz N, Pasini D, Diaz V, Franci C, Gutierrez A, Dave N . Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor. Mol Cell Biol. 2008; 28(15):4772-81. PMC: 2493371. DOI: 10.1128/MCB.00323-08. View

Yang J, Weinberg R . Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008; 14(6):818-29. DOI: 10.1016/j.devcel.2008.05.009. View

Simon M, Chu F, Racki L, de la Cruz C, Burlingame A, Panning B . The site-specific installation of methyl-lysine analogs into recombinant histones. Cell. 2007; 128(5):1003-12. PMC: 2932701. DOI: 10.1016/j.cell.2006.12.041. View

Taverna S, Li H, Ruthenburg A, Allis C, Patel D . How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol. 2007; 14(11):1025-1040. PMC: 4691843. DOI: 10.1038/nsmb1338. View

Koizume S, Tachibana K, Sekiya T, Hirohashi S, Shiraishi M . Heterogeneity in the modification and involvement of chromatin components of the CpG island of the silenced human CDH1 gene in cancer cells. Nucleic Acids Res. 2002; 30(21):4770-80. PMC: 135805. DOI: 10.1093/nar/gkf593. View

Nielsen P, Nietlispach D, Mott H, Callaghan J, Bannister A, Kouzarides T . Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9. Nature. 2002; 416(6876):103-7. DOI: 10.1038/nature722. View

Dong K, Maksakova I, Mohn F, Leung D, Appanah R, Lee S . DNA methylation in ES cells requires the lysine methyltransferase G9a but not its catalytic activity. EMBO J. 2008; 27(20):2691-701. PMC: 2572176. DOI: 10.1038/emboj.2008.193. View

10.

Kouzarides T . Chromatin modifications and their function. Cell. 2007; 128(4):693-705. DOI: 10.1016/j.cell.2007.02.005. View

11.

Shi Y, Sawada J, Sui G, Affar E, Whetstine J, Lan F . Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature. 2003; 422(6933):735-8. DOI: 10.1038/nature01550. View

12.

Vakoc C, Mandat S, Olenchock B, Blobel G . Histone H3 lysine 9 methylation and HP1gamma are associated with transcription elongation through mammalian chromatin. Mol Cell. 2005; 19(3):381-91. DOI: 10.1016/j.molcel.2005.06.011. View

13.

Graff J, Gabrielson E, Fujii H, Baylin S, Herman J . Methylation patterns of the E-cadherin 5' CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. J Biol Chem. 2000; 275(4):2727-32. DOI: 10.1074/jbc.275.4.2727. View

14.

Norwood L, Moss T, Margaryan N, Cook S, Wright L, Seftor E . A requirement for dimerization of HP1Hsalpha in suppression of breast cancer invasion. J Biol Chem. 2006; 281(27):18668-76. DOI: 10.1074/jbc.M512454200. View

15.

Jenuwein T, Allis C . Translating the histone code. Science. 2001; 293(5532):1074-80. DOI: 10.1126/science.1063127. View

16.

Reinhold W, Reimers M, Maunakea A, Kim S, Lababidi S, Scherf U . Detailed DNA methylation profiles of the E-cadherin promoter in the NCI-60 cancer cells. Mol Cancer Ther. 2007; 6(2):391-403. DOI: 10.1158/1535-7163.MCT-06-0609. View

17.

Peinado H, Ballestar E, Esteller M, Cano A . Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol Cell Biol. 2003; 24(1):306-19. PMC: 303344. DOI: 10.1128/MCB.24.1.306-319.2004. View

18.

Li H, Rauch T, Chen Z, Szabo P, Riggs A, Pfeifer G . The histone methyltransferase SETDB1 and the DNA methyltransferase DNMT3A interact directly and localize to promoters silenced in cancer cells. J Biol Chem. 2006; 281(28):19489-500. DOI: 10.1074/jbc.M513249200. View

19.

Onder T, Gupta P, Mani S, Yang J, Lander E, Weinberg R . Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 2008; 68(10):3645-54. DOI: 10.1158/0008-5472.CAN-07-2938. View

20.

Wang G, Allis C, Chi P . Chromatin remodeling and cancer, Part I: Covalent histone modifications. Trends Mol Med. 2007; 13(9):363-72. DOI: 10.1016/j.molmed.2007.07.003. View