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MBD2-Mediated Transcriptional Repression of the <i>p14</i>^ARF Tumor Suppressor Gene in Human Colon Cancer Cells

2008; Karger Publishers; Volume: 75; Issue: 5 Linguagem: Inglês

10.1159/000151708

1423-0291

Valérie Martin, Helle F. Jørgensen, Audrey S. Baur Chaubert, Jennifer Berger, Helen Barr, Phillip Shaw, Adrian Bird, Pascal Chaubert,

RNA modifications and cancer

<i>Objective:</i> The <i>p14</i>^ARF and <i>p16</i>^INK4A tumor suppressor genes are commonly inactivated by aberrant methylation of their promoter regions in human colon cancer. The methyl-CpG-binding domain protein MBD2 is physically associated with the methylated promoters of the <i>p14</i>^ARF and <i>p16</i>^INK4A genes in specific tumor cell lines. Moreover, deficiency of MBD2 strongly inhibits intestinal tumorigenesis in the Min mouse, raising the possibility that the protein might be involved in transcriptional repression of methylated tumor suppressor genes. The aim of this study was to evaluate the role of MBD2 in the silencing of <i>p14</i>^ARF and <i>p16</i>^INK4A in cancer. <i>Methods:</i> The MBD2 protein was stably knocked down by RNA interference in RKO, a colon cancer cell line in which both <i>p14</i>^ARF and <i>p16</i>^INK4A are silenced by methylation. <i>Results:</i> We demonstrate here that MBD2 associates with the methylated promoter of the <i>p14</i>^ARF gene in the RKO colon cancer cell line. Depletion of MBD2 by RNAi leads to selective upregulation of the <i>p14</i>^ARF but not the <i>p16</i>^INK4A gene transcript. In addition, p14^ARF repression can be restored by expressing mouse MBD2 protein in MBD2-deficient RKO cells. <i>Conclusion:</i> These findings implicate MBD2 in transcriptional repression of the methylated <i>p14</i>^ARF tumor suppressor gene and suggest that repression by MBD2 selectively affects a subset of methylated promoters.