Epigenetic changes in tumor Fas levels determine immune escape and response to therapy.
Epigenetic regulation of gene expression significantly influences cell growth and differentiation. Here we show that epigenetic silencing of Fas determines tumor growth in vivo and apoptotic sensitivity in vitro. In established tumors with epigenetically repressed Fas, restoration of Fas activity either by transfection of fas or treatment with Trichostatin A (TSA), an inhibitor of histone deacetylase, suppresses tumor growth and restores chemosensitivity. The TSA-dependent chemosensitivity and tumor growth control require both tumor Fas and the host NK (natural killer) cell functions. This work demonstrates the importance of epigenetic modification of Fas in tumor progression and immune evasion, and emphasizes the essential interplay between Fas and innate immunity in the control of chemoresistant tumors.
Department of Radiation Oncology, Stanford University Medical Center, CCSR South, 269 Campus Drive, Stanford, California 94305, USA. hmaecker@gene.com
Heather L
HL
Maecker
Zhong
Z
Yun
Holden T
HT
Maecker
Amato J
AJ
Giaccia
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D015395:Histocompatibility Antigens Class I; D006877:Hydroxamic Acids; D019014:fas Receptor; C012589:trichostatin A