Abstract
Dysfunctional telomeres suppress tumour progression by activating cell-intrinsic programs that lead to growth arrest. Increased levels of TRF2, a key factor in telomere protection, are observed in various human malignancies and contribute to oncogenesis. We demonstrate here that a high level of TRF2 in tumour cells decreased their ability to recruit and activate natural killer (NK) cells. Conversely, a reduced dose of TRF2 enabled tumour cells to be more easily eliminated by NK cells. Consistent with these results, a progressive upregulation of TRF2 correlated with decreased NK cell density during the early development of human colon cancer. By screening for TRF2-bound genes, we found that HS3ST4--a gene encoding for the heparan sulphate (glucosamine) 3-O-sulphotransferase 4--was regulated by TRF2 and inhibited the recruitment of NK cells in an epistatic relationship with TRF2. Overall, these results reveal a TRF2-dependent pathway that is tumour-cell extrinsic and regulates NK cell immunity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Blotting, Western
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Breast Neoplasms / immunology
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Breast Neoplasms / metabolism
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Breast Neoplasms / prevention & control*
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Cell Adhesion
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Cell Proliferation
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Colonic Neoplasms / immunology
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / prevention & control*
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DNA Primers / chemistry
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Discoidin Domain Receptor 1
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Female
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Flow Cytometry
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HeLa Cells
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Humans
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Killer Cells, Natural / pathology
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Lymphocytes, Tumor-Infiltrating / immunology*
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Lymphocytes, Tumor-Infiltrating / pathology
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Melanoma, Experimental / immunology
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Melanoma, Experimental / metabolism
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Melanoma, Experimental / prevention & control*
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Mice
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Mice, Nude
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Real-Time Polymerase Chain Reaction
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sulfotransferases / genetics
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Sulfotransferases / metabolism*
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Telomeric Repeat Binding Protein 2 / antagonists & inhibitors
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Telomeric Repeat Binding Protein 2 / genetics
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Telomeric Repeat Binding Protein 2 / metabolism*
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Tumor Cells, Cultured
Substances
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DNA Primers
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RNA, Messenger
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RNA, Small Interfering
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Telomeric Repeat Binding Protein 2
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DDR1 protein, human
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Discoidin Domain Receptor 1
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Receptor Protein-Tyrosine Kinases
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Sulfotransferases
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heparitin sulfotransferase