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.
TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells / Annamaria, Biroccio; Julien Cherfils, Vicini; Adeline, Augereau; Sebastien, Pinte; Serge, Bauwens; Jing, Ye; Thomas, Simonet; Beatrice, Horard; Karine, Jamet; Ludovic, Cervera; Aaron Mendez, Bermudez; Delphine, Poncet; Renee, Grataroli; Claire T’kint De, Rodenbeeke; Erica, Salvati; Angela, Rizzo; Pasquale, Zizza; Michelle, Ricoul; Celine, Cognet; Thomas, Kuilman; Helene, Duret; Florian, Lepinasse; Jacqueline, Marvel; Els, Verhoeyen; Francois Loic, Cosset; Daniel, Peeper; Mark J., Smyth; Arturo Londono, Vallejo; Laure, Sabatier; Vincent, Picco; Gilles, Pages; Jean Yves, Scoazec; Stoppacciaro, Antonella; Carlo, Leonetti; Eric, Vivier; Eric, Gilson. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - STAMPA. - 15:7(2013), pp. 818-828. [10.1038/ncb2774]
TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells
STOPPACCIARO, ANTONELLA;
2013
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.