SMYD3 Promotes Cancer Invasion by Epigenetic Upregulation of the Metalloproteinase MMP-9

Université Paris Diderot, Sorbonne Paris Cité, CNRS UMR7216 Epigénétique et Destin Cellulaire, Université Paris Descartes, Sorbonne Paris Cité, Inserm U1016, Paris, France.
Cancer Research (Impact Factor: 9.33). 12/2011; 72(3):810-20. DOI: 10.1158/0008-5472.CAN-11-1052
Source: PubMed


Upregulation of the matrix metalloproteinase (MMP)-9 plays a central role in tumor progression and metastasis by stimulating cell migration, tumor invasion, and angiogenesis. To gain insights into MMP-9 expression, we investigated its epigenetic control in a reversible model of cancer that is initiated by infection with intracellular Theileria parasites. Gene induction by parasite infection was associated with trimethylation of histone H3K4 (H3K4me3) at the MMP-9 promoter. Notably, we found that the H3K4 methyltransferase SMYD3 was the only histone methyltransferase upregulated upon infection. SMYD3 is overexpressed in many types of cancer cells, but its contributions to malignant pathophysiology are unclear. We found that overexpression of SMYD3 was sufficient to induce MMP-9 expression in transformed leukocytes and fibrosarcoma cells and that proinflammatory phorbol esters further enhanced this effect. Furthermore, SMYD3 was sufficient to increase cell migration associated with MMP-9 expression. In contrast, RNA interference-mediated knockdown of SMYD3 decreased H3K4me3 modification of the MMP-9 promoter, reduced MMP-9 expression, and reduced tumor cell proliferation. Furthermore, SMYD3 knockdown also reduced cellular invasion in a zebrafish xenograft model of cancer. Together, our results define SMYD3 as an important new regulator of MMP-9 transcription, and they provide a molecular link between SMYD3 overexpression and metastatic cancer progression.

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    • "In contrast, BL20 showed no detectable effect of BW720c on the rate of division. A similar growth arrest phenotype following BW720c treatment was recently described for T. annulata infected cells derived from a different immortalised host cell line [36], indicating that the result is not restricted to the BL20 host cell background. Estimation of caspase 3/7 activity, a marker of progression towards apoptosis, showed a significant increase in the TBL20 BW720c-treated culture that was not detected in control (no drug) TBL20 cells or uninfected BL20 cells. "
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    PLoS ONE 06/2013; 8(6):e66833. DOI:10.1371/journal.pone.0066833 · 3.23 Impact Factor
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    • "SMYD3 is also a transcription factor that specifically interacts with the binding motif/s of its downstream genes. Endogenous expression of SMYD3 is undetectable or very weak in most normal human tissues whereas significant up-regulation was observed in the great majority of investigated colorectal carcinoma, hepatocellular carcinoma, and breast cancer specimens [24], [25]. SMCX, also known as KDM5C or JARID1C, has H3-K4 tri-demethylase activity and reverses H3-K4 to di- and mono- but not unmethylated products, and thereby functions as a transcriptional repressor [26]. "
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    PLoS ONE 12/2012; 7(12):e52703. DOI:10.1371/journal.pone.0052703 · 3.23 Impact Factor
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    • "Moreover, the use of multifluorescent transgenic animals will allow for labeling of tumor cell compartments similar to those defined in RASinduced rhabdomyosarcoma models [21] [50] and for the visualizing of leukemia growth in relation to supportive cell types including vasculature, fibroblasts, and macrophages. Moreover, though not the focus of this paper, cell transplantation approaches that utilize fluorescently labeled, human leukemia cells into either zebrafish embryos or adults will likely provide novel experimental models to assess tumor growth and response to therapy [51] [52] [53] [54] [55] [56] [57] [58] [59] [60], capitalizing on the numbers of disease animals that can be created by microinjection and direct visualization of tumor growth in vivo. "
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    Advances in Hematology 07/2012; 2012(8):478164. DOI:10.1155/2012/478164
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