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Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-κB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes

Oncogene volume 28, pages 1626–1638 (2009)Cite this article

Abstract

Constitutive nuclear factor (NF)-κB activation in haematological malignancies is caused in several cases by loss of function mutations within the coding sequence of NF-κB inhibitory molecules such as IκBα or p100. Hut-78, a truncated form of p100, constitutively generates p52 and contributes to the development of T-cell lymphomas but the molecular mechanism underlying this oncogenic potential remains unclear. We show here that MMP9 gene expression is induced through the alternative NF-κB-activating pathway in fibroblasts and also on Hut-78 or p52 overexpression in fibroblasts as well as in lymphoma cells. p52 is critical for Hut-78-mediated MMP9 gene induction as a Hut-78 mutant as well as other truncated NF-κB2 proteins that are not processed into p52 failed to induce the expression of this metalloproteinase. Conversely, MMP9 gene expression is impaired in p52-depleted HUT-78 cells. Interestingly, MLL1 and MLL2 H3K4 methyltransferase complexes are tethered by p52 on the MMP9 but not on the IκBα promoter, and the H3K4 trimethyltransferase activity recruited on the MMP9 promoter is impaired in p52-depleted HUT-78 cells. Moreover, MLL1 and MLL2 are associated with Hut-78 in a native chromatin-enriched extract. Thus, we identified a molecular mechanism by which the recruitment of a H3K4 histone methyltransferase complex on the promoter of a NF-κB-dependent gene induces its expression and potentially the invasive potential of lymphoma cells harbouring constitutive activity of the alternative NF-κB-activating pathway.

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References

  • Allis CD, Berger SL, Cote J, Dent S, Jenuwien T, Kouzarides T et al. (2007). New nomenclature for chromatin-modifying enzymes. Cell 131: 633–636.

    Article  CAS  PubMed  Google Scholar 

  • Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F et al. (2007). Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12: 115–130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aoudjit F, Potworowski EF, St-Pierre Y . (1998). The metastatic characteristics of murine lymphoma cell lines in vivo are manifested after target organ invasion. Blood 91: 623–629.

    CAS  PubMed  Google Scholar 

  • Aygun O, Svejstrup J, Liu Y . (2008). A RECQ5-RNA polymerase II association identified by targeted proteomic analysis of human chromatin. Proc Natl Acad Sci USA 105: 8580–8584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berger SL . (2007). The complex language of chromatin regulation during transcription. Nature 447: 407–412.

    Article  CAS  PubMed  Google Scholar 

  • Bhaumik SR, Smith E, Shilatifard A . (2007). Covalent modifications of histones during development and disease pathogenesis. Nat Struct Mol Biol 14: 1008–1016.

    Article  CAS  PubMed  Google Scholar 

  • Bonizzi G, Karin M . (2004). The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25: 280–288.

    Article  CAS  PubMed  Google Scholar 

  • Bours V, Franzoso G, Azarenko V, Park S, Kanno T, Brown K et al. (1993). The oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers. Cell 72: 729–739.

    Article  CAS  PubMed  Google Scholar 

  • Briggs SD, Bryk M, Strahl BD, Cheung WL, Davie JK, Dent SY et al. (2001). Histone H3 lysine 4 methylation is mediated by Set1 and required for cell growth and rDNA silencing in Saccharomyces cerevisiae. Genes Dev 15: 3286–3295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cabannes E, Khan G, Aillet F, Jarrett RF, Hay RT . (1999). Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role for IkappaBalpha. Oncogene 18: 3063–3070.

    Article  CAS  PubMed  Google Scholar 

  • Chang CC, Zhang J, Lombardi L, Neri A, Dalla-Favera R . (1995). Rearranged NFKB-2 genes in lymphoid neoplasms code for constitutively active nuclear transactivators. Mol Cell Biol 15: 5180–5187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Claudio E, Brown K, Park S, Wang H, Siebenlist U . (2002). BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells. Nat Immunol 3: 958–965.

    Article  CAS  PubMed  Google Scholar 

  • Coope HJ, Atkinson PG, Huhse B, Belich M, Janzen J, Holman MJ et al. (2002). CD40 regulates the processing of NF-kappaB2 p100 to p52. EMBO J 21: 5375–5385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Courtois G, Gilmore TD . (2006). Mutations in the NF-kappaB signaling pathway: implications for human disease. Oncogene 25: 6831–6843.

    Article  CAS  PubMed  Google Scholar 

  • De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G . (2007). The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130: 1083–1094.

    Article  CAS  PubMed  Google Scholar 

  • Dejardin E, Droin NM, Delhase M, Haas E, Cao Y, Makris C et al. (2002). The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. Immunity 17: 525–535.

    Article  CAS  PubMed  Google Scholar 

  • Derudder E, Laferte A, Ferreira V, Mishal Z, Baud V, Tarantino N et al. (2003). Identification and characterization of p100HB, a new mutant form of p100/NF-kappa B2. Biochem Biophys Res Commun 308: 744–749.

    Article  CAS  PubMed  Google Scholar 

  • Emmerich F, Meiser M, Hummel M, Demel G, Foss HD, Jundt F et al. (1999). Overexpression of I kappa B alpha without inhibition of NF-kappaB activity and mutations in the I kappa B alpha gene in Reed-Sternberg cells. Blood 94: 3129–3134.

    CAS  PubMed  Google Scholar 

  • Epinat JC, Kazandjian D, Harkness DD, Petros S, Dave J, White DW et al. (2000). Mutant envelope residues confer a transactivation function onto N-terminal sequences of the v-Rel oncoprotein. Oncogene 19: 599–607.

    Article  CAS  PubMed  Google Scholar 

  • Fracchiolla NS, Lombardi L, Salina M, Migliazza A, Baldini L, Berti E et al. (1993). Structural alterations of the NF-kappa B transcription factor lyt-10 in lymphoid malignancies. Oncogene 8: 2839–2845.

    CAS  PubMed  Google Scholar 

  • Glaser S, Schaft J, Lubitz S, Vintersten K, van der Hoeven F, Tufteland KR et al. (2006). Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development. Development 133: 1423–1432.

    Article  CAS  PubMed  Google Scholar 

  • Hayden MS, Ghosh S . (2008). Shared principles in NF-kappaB signaling. Cell 132: 344–362.

    Article  CAS  PubMed  Google Scholar 

  • Heissig B, Hattori K, Friedrich M, Rafii S, Werb Z . (2003). Angiogenesis: vascular remodeling of the extracellular matrix involves metalloproteinases. Curr Opin Hematol 10: 136–141.

    Article  CAS  PubMed  Google Scholar 

  • Hughes CM, Rozenblatt-Rosen O, Milne TA, Copeland TD, Levine SS, Lee JC et al. (2004). Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell 13: 587–597.

    Article  CAS  PubMed  Google Scholar 

  • Ishikawa H, Carrasco D, Claudio E, Ryseck RP, Bravo R . (1997). Gastric hyperplasia and increased proliferative responses of lymphocytes in mice lacking the COOH-terminal ankyrin domain of NF-kappaB2. J Exp Med 186: 999–1014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jost PJ, Ruland J . (2007). Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood 109: 2700–2707.

    CAS  PubMed  Google Scholar 

  • Jungnickel B, Staratschek-Jox A, Brauninger A, Spieker T, Wolf J, Diehl V et al. (2000). Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin's lymphoma. J Exp Med 191: 395–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karin M, Lin A . (2002). NF-kappaB at the crossroads of life and death. Nat Immunol 3: 221–227.

    Article  CAS  PubMed  Google Scholar 

  • Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ et al. (2007). Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 12: 131–144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keutgens A, Robert I, Viatour P, Chariot A . (2006). Deregulated NF-kappaB activity in haematological malignancies. Biochem Pharmacol 72: 1069–1080.

    Article  CAS  PubMed  Google Scholar 

  • Kim KE, Gu C, Thakur S, Vieira E, Lin JC, Rabson AB . (2000). Transcriptional regulatory effects of lymphoma-associated NFKB2/lyt10 protooncogenes. Oncogene 19: 1334–1345.

    Article  CAS  PubMed  Google Scholar 

  • Klose RJ, Kallin EM, Zhang Y . (2006). JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet 7: 715–727.

    Article  CAS  PubMed  Google Scholar 

  • Klose RJ, Yan Q, Tothova Z, Yamane K, Erdjument-Bromage H, Tempst P et al. (2007). The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 128: 889–900.

    Article  CAS  PubMed  Google Scholar 

  • Kouskouti A, Talianidis I . (2005). Histone modifications defining active genes persist after transcriptional and mitotic inactivation. EMBO J 24: 347–357.

    Article  CAS  PubMed  Google Scholar 

  • Lalancette M, Aoudjit F, Potworowski EF, St-Pierre Y . (2000). Resistance of ICAM-1-deficient mice to metastasis overcome by increased aggressiveness of lymphoma cells. Blood 95: 314–319.

    CAS  PubMed  Google Scholar 

  • Li Q, Verma IM . (2002). NF-kappaB regulation in the immune system. Nat Rev Immunol 2: 725–734.

    Article  CAS  PubMed  Google Scholar 

  • McKeithan TW, Rowley JD, Shows TB, Diaz MO . (1987). Cloning of the chromosome translocation breakpoint junction of the t(14;19) in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 84: 9257–9260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miller T, Krogan NJ, Dover J, Erdjument-Bromage H, Tempst P, Johnston M et al. (2001). COMPASS: a complex of proteins associated with a trithorax-related SET domain protein. Proc Natl Acad Sci USA 98: 12902–12907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mori N, Sato H, Hayashibara T, Senba M, Hayashi T, Yamada Y et al. (2002). Human T-cell leukemia virus type I Tax transactivates the matrix metalloproteinase-9 gene: potential role in mediating adult T-cell leukemia invasiveness. Blood 99: 1341–1349.

    Article  CAS  PubMed  Google Scholar 

  • Nagy PL, Griesenbeck J, Kornberg RD, Cleary ML . (2002). A trithorax-group complex purified from Saccharomyces cerevisiae is required for methylation of histone H3. Proc Natl Acad Sci USA 99: 90–94.

    Article  CAS  PubMed  Google Scholar 

  • Neri A, Chang CC, Lombardi L, Salina M, Corradini P, Maiolo AT et al. (1991). B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-kappa B p50. Cell 67: 1075–1087.

    Article  CAS  PubMed  Google Scholar 

  • Noma K, Grewal SI . (2002). Histone H3 lysine 4 methylation is mediated by Set1 and promotes maintenance of active chromatin states in fission yeast. Proc Natl Acad Sci USA 99 (Suppl 4): 16438–16445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perkins ND . (2007). Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol 8: 49–62.

    Article  CAS  PubMed  Google Scholar 

  • Qing G, Qu Z, Xiao G . (2007). Endoproteolytic processing of C-terminally truncated NF-kappaB2 precursors at kappaB-containing promoters. Proc Natl Acad Sci USA 104: 5324–5329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Redondo-Munoz J, Escobar-Diaz E, Samaniego R, Terol MJ, Garcia-Marco JA, Garcia-Pardo A . (2006). MMP-9 in B-cell chronic lymphocytic leukemia is up-regulated by alpha4beta1 integrin or CXCR4 engagement via distinct signaling pathways, localizes to podosomes, and is involved in cell invasion and migration. Blood 108: 3143–3151.

    Article  CAS  PubMed  Google Scholar 

  • Ruthenburg AJ, Allis CD, Wysocka J . (2007). Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol Cell 25: 15–30.

    Article  CAS  PubMed  Google Scholar 

  • Saitoh Y, Yamamoto N, Dewan MZ, Sugimoto H, Martinez Bruyn VJ, Iwasaki Y et al. (2008). Overexpressed NF-kappaB-inducing kinase contributes to the tumorigenesis of adult T-cell leukemia and Hodgkin Reed-Sternberg cells. Blood 111: 5118–5129.

    Article  CAS  PubMed  Google Scholar 

  • Sakata K, Satoh M, Someya M, Asanuma H, Nagakura H, Oouchi A et al. (2004). Expression of matrix metalloproteinase 9 is a prognostic factor in patients with non-Hodgkin lymphoma. Cancer 100: 356–365.

    Article  CAS  PubMed  Google Scholar 

  • Santos-Rosa H, Schneider R, Bannister AJ, Sherriff J, Bernstein BE, Emre NC et al. (2002). Active genes are tri-methylated at K4 of histone H3. Nature 419: 407–411.

    Article  CAS  PubMed  Google Scholar 

  • Shilatifard A . (2006). Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu Rev Biochem 75: 243–269.

    Article  CAS  PubMed  Google Scholar 

  • Shim JH, Xiao C, Paschal AE, Bailey ST, Rao P, Hayden MS et al. (2005). TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev 19: 2668–2681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siebenlist U, Brown K, Claudio E . (2005). Control of lymphocyte development by nuclear factor-kappaB. Nat Rev Immunol 5: 435–445.

    Article  CAS  PubMed  Google Scholar 

  • Srivastava AK, Qin X, Wedhas N, Arnush M, Linkhart TA, Chadwick RB et al. (2007). Tumor necrosis factor-alpha augments matrix metalloproteinase-9 production in skeletal muscle cells through the activation of transforming growth factor-beta-activated kinase 1 (TAK1)-dependent signaling pathway. J Biol Chem 282: 35113–35124.

    Article  CAS  PubMed  Google Scholar 

  • Thakur S, Lin HC, Tseng WT, Kumar S, Bravo R, Foss F et al. (1994). Rearrangement and altered expression of the NFKB-2 gene in human cutaneous T-lymphoma cells. Oncogene 9: 2335–2344.

    CAS  PubMed  Google Scholar 

  • Viatour P, Dejardin E, Warnier M, Lair F, Claudio E, Bureau F et al. (2004). GSK3-mediated BCL-3 phosphorylation modulates its degradation and its oncogenicity. Mol Cell 16: 35–45.

    Article  CAS  PubMed  Google Scholar 

  • Viatour P, Legrand-Poels S, van Lint C, Warnier M, Merville MP, Gielen J et al. (2003). Cytoplasmic IkappaBalpha increases NF-kappaB-independent transcription through binding to histone deacetylase (HDAC) 1 and HDAC3. J Biol Chem 278: 46541–46548.

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Zhang B, Yang L, Ding J, Ding HF . (2008). Constitutive production of NF-kappaB2 p52 is not tumorigenic but predisposes mice to inflammatory autoimmune disease by repressing Bim expression. J Biol Chem 283: 10698–10706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiao G, Harhaj EW, Sun SC . (2001). NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell 7: 401–409.

    Article  CAS  PubMed  Google Scholar 

  • Yoshizaki T, Sato H, Furukawa M, Pagano JS . (1998). The expression of matrix metalloproteinase 9 is enhanced by Epstein-Barr virus latent membrane protein 1. Proc Natl Acad Sci USA 95: 3621–3626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang B, Wang Z, Li T, Tsitsikov EN, Ding HF . (2007). NF-kappaB2 mutation targets TRAF1 to induce lymphomagenesis. Blood 110: 743–751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Chang CC, Lombardi L, Dalla-Favera R . (1994). Rearranged NFKB2 gene in the HUT78 T-lymphoma cell line codes for a constitutively nuclear factor lacking transcriptional repressor functions. Oncogene 9: 1931–1937.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to F Fuks for helpful discussions, to M Pasparakis, Y St-Pierre and R Weil for the gifts of wild-type and NEMO-deficient mouse embryonic fibroblasts, the 164T2 cell line and the anti-NEMO antibody, respectively. We also thank Dr J-H Lee, Dr DG Skalnik and Dr C van Lint for the gift of expression plasmids. M-PM, LdeL and AC are Senior Research Associates whereas ED is Research Associate at the Belgian National fund for Research (‘FNRS’). IR and XZ are ‘TELEVIE’ Research Assistants whereas MA and AK are ‘FNRS’ Research Assistants. This work was supported by grants from the University of Liege (ULg), FNRS, TELEVIE, the Belgian Federation against Cancer, the IAP6/18 (funded by the Interuniversity Attraction Poles Programme, initiated by the Belgian State, Science Policy Office), the ‘Centre Anti-Cancéreux’ and ‘Fonds Léon Frédéricq’ (Faculty of Medicine, ULg).

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Authors and Affiliations

  1. Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), CHU, Sart-Tilman, University of Liege, Liege, Belgium

    I Robert, M Aussems, A Keutgens, X Zhang, B Hennuy, P Viatour, G Vanstraelen, M-P Merville, J-P Chapelle, L de Leval, F Lambert, E Dejardin, A Gothot & A Chariot

  2. GIGA Signal Transduction, CHU, Sart-Tilman, University of Liege, Liege, Belgium

    I Robert, M Aussems, A Keutgens, X Zhang, P Viatour, M-P Merville, J-P Chapelle, E Dejardin & A Chariot

  3. Laboratory of Medical Chemistry, CHU, Sart-Tilman, University of Liege, Liege, Belgium

    I Robert, M Aussems, A Keutgens, X Zhang, P Viatour, M-P Merville, J-P Chapelle & A Chariot

  4. GIGA Transcriptomics Facility, CHU, Sart-Tilman, University of Liege, Liege, Belgium

    B Hennuy

  5. Department of Medicine/Hematology, CHU, Sart-Tilman, University of Liege, Liege, Belgium

    G Vanstraelen & A Gothot

  6. Department of Pathology, CHU, Sart-Tilman, University of Liege, Liege, Belgium

    L de Leval

  7. Laboratory of Human Genetics, CHU, Sart-Tilman, University of Liege, Liege, Belgium

    F Lambert

  8. Laboratory of Virology and Immunology, CHU, Sart-Tilman, University of Liege, Liege, Belgium

    E Dejardin

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Robert, I., Aussems, M., Keutgens, A. et al. Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-κB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes. Oncogene 28, 1626–1638 (2009). https://doi.org/10.1038/onc.2009.6

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