[en] Membrane type-1 matrix metalloproteinase (MT1-MMP) is an activator of soluble MMP-2. The activity of both MMPs is regulated by their physiological inhibitor TIMP-2. An MT1-MMP/MMP-2/TIMP-2 axis plays a key role in the invasive behavior of many cell types. Despite its importance, epigenetic control of this pro-invasive axis is insufficiently studied, and, as a result, its modification in a rational and clinically beneficial manner is exceedingly difficult. Therefore, we performed an epigenetic analysis of the MT1-MMP, MMP-2, and TIMP-2 gene promoters in highly migratory glioblastoma cells and in low migratory breast carcinoma MCF-7 cells. We determined, for the first time, that the epigenetic control leading to the transcriptional silencing of both MMPs includes hypermethylation of the corresponding CpG regions and histone H3 lysine-27 trimethylation (H3K27me3). In turn, undermethylation of the CpG islands and low levels of histone H3 lysine-27 trimethylation are features of transcriptionally active MT1-MMP and MMP-2 genes in invasive cancer cells. Additional histone modifications we have analyzed, including H3ac and H3K4me2, are present in both transcriptionally active and inactive promoters of both MMPs. Histone H3 lysine-4 trimethylation is likely to play no significant role in regulating MT1-MMP and MMP-2. The pattern of epigenetic regulation of TIMP-2 was clearly distinct from that of MMPs and included the coordinated methylation and demethylation of the two CpG regions in the promoter. Our results suggest that the epigenetic control plays an important role in both the balanced regulation of the MT1-MMP/MMP-2/TIMP-2 axis and the invasive behavior in cancer cells.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Chernov, Andrei V.
Sounni, Nor Eddine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Remacle, Albert G.
Strongin, Alex Y.
Language :
English
Title :
Epigenetic control of the invasion-promoting MT1-MMP/MMP-2/TIMP-2 axis in cancer cells
Publication date :
2009
Journal title :
Journal of Biological Chemistry
ISSN :
0021-9258
eISSN :
1083-351X
Publisher :
American Society for Biochemistry and Molecular Biology, Baltimore, United States - Maryland
Friedl, P., and Wolf, K. (2008) Cancer Res. 68, 7247-7249
Egeblad, M., and Werb, Z. (2002) Nat. Rev. Cancer 2, 161-174
Itoh, Y. (2006) IUBMB Life 58, 589-596
Seidah, N. G., Mayer, G., Zaid, A., Rousselet, E., Nassoury, N., Poirier, S., Essalmani, R., and Prat, A. (2008) Int. J. Biochem. Cell Biol. 40, 1111-1125
Osenkowski, P., Toth, M., and Fridman, R. (2004) J. Cell. Physiol. 200, 2-10
Strongin, A. Y. (2006) Cancer Metastasis Rev. 25, 87-98
Murphy, G., Stanton, H., Cowell, S., Butler, G., Knauper, V., Atkinson, S., and Gavrilovic, J. (1999) APMIS 107, 38-44
Clark, I. M., Swingler, T. E., Sampieri, C. L., and Edwards, D. R. (2008) Int. J. Biochem. Cell Biol. 40, 1362-1378
Noel, A., Maillard, C., Rocks, N., Jost, M., Chabottaux, V., Sounni, N. E., Maquoi, E., Cataldo, D., and Foidart, J. M. (2004) J. Clin. Pathol. 57, 577-584
Fry, C. J., and Peterson, C. L. (2001) Curr. Biol. 11, R185-197
Turner, B. M. (2005) Nat. Struct. Mol. Biol. 12, 110-112
Swigut, T., and Wysocka, J. (2007) Cell 131, 29-32
Zhang, Y., and Reinberg, D. (2001) Genes Dev. 15, 2343-2360
Kouzarides, T. (2007) Cell 128, 693-705
Bannister, A. J., Zegerman, P., Partridge, J. F., Miska, E. A., Thomas, J. O., Allshire, R. C., and Kouzarides, T. (2001) Nature 410, 120-124
Lachner, M., O'Carroll, D., Rea, S., Mechtler, K., and Jenuwein, T. (2001) Nature 410, 116-120
Nakayama, J., Rice, J. C., Strahl, B. D., Allis, C. D., and Grewal, S. I. (2001) Science 292, 110-113
Peters, A. H., Mermoud, J. E., O'Carroll, D., Pagani, M., Schweizer, D., Brockdorff, N., and Jenuwein, T. (2002) Nat. Genet. 30, 77-80
Azuara, V., Perry, P., Sauer, S., Spivakov, M., Jorgensen, H. F., John, R. M., Gouti, M., Casanova, M., Warnes, G., Merkenschlager, M., and Fisher, A. G. (2006) Nat. Cell Biol. 8, 532-538
Bernstein, B. E., Mikkelsen, T. S., Xie, X., Kamal, M., Huebert, D. J., Cuff, J., Fry, B., Meissner, A., Wernig, M., Plath, K., Jaenisch, R., Wagschal, A., Feil, R., Schreiber, S. L., and Lander, E. S. (2006) Cell 125, 315-326
Chicoine, E., Esteve, P. O., Robledo, O., Van Themsche, C., Potworowski, E. F., and St-Pierre, Y. (2002) Biochem. Biophys. Res. Commun. 297, 765-772
Clark, I. M., Swingler, T. E., and Young, D. A. (2007) Front. Biosci. 12, 528-535
Pulukuri, S. M., Patibandla, S., Patel, J., Estes, N., and Rao, J. S. (2007) Oncogene 26, 5229-5237
Roach, H. I., Yamada, N., Cheung, K. S., Tilley, S., Clarke, N. M., Oreffo, R. O., Kokubun, S., and Bronner, F. (2005) Arthritis Rheum. 52, 3110-3124
Deryugina, E. I., Bourdon, M. A., Luo, G. X., Reisfeld, R. A., and Strongin, A. (1997) J. Cell Sci. 110, 2473-2482
Golubkov, V. S., Chekanov, A. V., Doxsey, S. J., and Strongin, A. Y. (2005) J. Biol. Chem. 280, 42237-42241
Li, L. C., and Dahiya, R. (2002) Bioinformatics 18, 1427-1431
Rozen, S., and Skaletsky, H. (2000) Methods Mol. Biol. 132, 365-386
Abd El-Aziz, S. H., Endo, Y., Miyamaori, H., Takino, T., and Sato, H. (2007) Cancer Sci. 98, 1330-1335
Atkinson, S. J., Roghi, C., and Murphy, G. (2006) Biochem. J. 398, 15-22
Deryugina, E. I., Ratnikov, B. I., Postnova, T. I., Rozanov, D. V., and Strongin, A. Y. (2002) J. Biol. Chem. 277, 9749-9756
Ratnikov, B. I., Rozanov, D. V., Postnova, T. I., Baciu, P. G., Zhang, H., DiScipio, R. G., Chestukhina, G. G., Smith, J. W., Deryugina, E. I., and Strongin, A. Y. (2002) J. Biol. Chem. 277, 7377-7385
Rozanov, D. V., Deryugina, E. I., Ratnikov, B. I., Monosov, E. Z., Marchenko, G. N., Quigley, J. P., and Strongin, A. Y. (2001) J. Biol. Chem. 276, 25705-25714
Sounni, N. E., Roghi, C., Chabottaux, V., Janssen, M., Munaut, C., Maquoi, E., Galvez, B. G., Gilles, C., Frankenne, F., Murphy, G., Foidart, J. M., and Noel, A. (2004) J. Biol. Chem. 279, 13564-13574
Barski, A., Cuddapah, S., Cui, K., Roh, T. Y., Schones, D. E., Wang, Z., Wei, G., Chepelev, I., and Zhao, K. (2007) Cell 129, 823-837
Zhao, X. D., Han, X., Chew, J. L., Liu, J., Chiu, K. P., Choo, A., Orlov, Y. L., Sung, W. K., Shahab, A., Kuznetsov, V. A., Bourque, G., Oh, S., Ruan, Y., Ng, H. H., and Wei, C. L. (2007) Cell Stem Cell 1, 286-298
Bernstein, B. E., Humphrey, E. L., Erlich, R. L., Schneider, R., Bouman, P., Liu, J. S., Kouzarides, T., and Schreiber, S. L. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 8695-8700
Strongin, A. Y., Collier, I., Bannikov, G., Marmer, B. L., Grant, G. A., and Goldberg, G. I. (1995) J. Biol. Chem. 270, 5331-5338
Itoh, T., Ikeda, T., Gomi, H., Nakao, S., Suzuki, T., and Itohara, S. (1997) J. Biol. Chem. 272, 22389-22392
Holmbeck, K., Bianco, P., Caterina, J., Yamada, S., Kromer, M., Kuznetsov, S. A., Mankani, M., Robey, P. G., Poole, A. R., Pidoux, I., Ward, J. M., and Birkedal-Hansen, H. (1999) Cell 99, 81-92
Oh, J., Takahashi, R., Adachi, E., Kondo, S., Kuratomi, S., Noma, A., Alexander, D. B., Motoda, H., Okada, A., Seiki, M., Itoh, T., Itohara, S., Takahashi, C., and Noda, M. (2004) Oncogene 23, 5041-5048
Boyer, L. A., Plath, K., Zeitlinger, J., Brambrink, T., Medeiros, L. A., Lee, T. I., Levine, S. S., Wernig, M., Tajonar, A., Ray, M. K., Bell, G. W., Otte, A. P., Vidal, M., Gifford, D. K., Young, R. A., and Jaenisch, R. (2006) Nature 441, 349-353
Lee, T. I., Jenner, R. G., Boyer, L. A., Guenther, M. G., Levine, S. S., Kumar, R. M., Chevalier, B., Johnstone, S. E., Cole, M. F., Isono, K., Koseki, H., Fuchikami, T., Abe, K., Murray, H. L., Zucker, J. P., Yuan, B., Bell, G. W., Herbolsheimer, E., Hannett, N. M., Sun, K., Odom, D. T., Otte, A. P., Volkert, T. L., Bartel, D. P., Melton, D. A., Gifford, D. K., Jaenisch, R., and Young, R. A. (2006) Cell 125, 301-313
Curtin, M., and Glaser, K. (2003) Curr. Med. Chem. 10, 2373-2392
Ohlsson, R., Renkawitz, R., and Lobanenkov, V. (2001) Trends Genet. 17, 520-527
