title: Reduction of Fas/CD95 promoter methylation, upregulation of Fas protein, and enhancement of sensitivity to apoptosis in cutaneous T-cell lymphoma.
abstract: OBJECTIVE
  To explore the relationships among (Fas) promoter methylation, Fas expression, and apoptotic sensitivity in cutaneous T-cell lymphoma (CTCL).
  
  
  METHODS
  Laboratory investigation.
  
  
  METHODS
  Dermatology research unit of a university medical center.
  
  
  METHODS
  Five CTCL lines and Sézary syndrome blood.
  
  
  METHODS
  Treatment of cells with 5-azacytidine (aza), methotrexate, and interferon alfa-2b.
  
  
  METHODS
  Fas promoter methylation, Fas expression, and sensitivity to Fas-mediated apoptosis.
  
  
  RESULTS
  Fas promoter methylation correlates inversely with the level of Fas transcript, protein, and apoptotic sensitivity in CTCL. Increased DNA methylation also correlates with decreased NFkB (nuclear factor kappa-light chain enhancer of activated B cells) binding to the Fas promoter. All of these relationships were reversed by the DNA-demethylating agent, 5-aza. We found that methotrexate also functions as a DNA-demethylating agent by depleting methyl donors and, together with interferon alfa-2b, upregulates Fas and enhances sensitivity to Fas-mediated apoptosis.
  
  
  CONCLUSIONS
  These findings help explain the previously reported impressive responses of patients with advanced CTCL to combination therapy with methotrexate and interferon alfa. They also provide a new rationale for the treatment of CTCL with methotrexate and its use in combination with other agents.
authors.affiliation: Departments of Dermatology, University of Wisconsin, and Veterans Affairs Medical Center, Madison, WI 53715, USA.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Wu
authors.forename: Gary S
authors.initials: GS
authors.lastname: Wood
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology / Q000627:therapeutic use; D016898:Interferon-alpha; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C491901:FAS protein, human; D007370:Interferon Type I; D016898:Interferon-alpha; D016328:NF-kappa B; D011994:Recombinant Proteins; D019014:fas Receptor; C076799:interferon-alpha 8; D001374:Azacitidine; D008727:Methotrexate