title: Transformation-dependent silencing of tumor-selective apoptosis-inducing TRAIL by DNA hypermethylation is antagonized by decitabine.
abstract: TNF-related apoptosis-inducing ligand (TRAIL) kills tumor cells selectively. We asked how emerging tumor cells escape elimination by TRAIL and how tumor-specific killing by TRAIL could then be restored. We found that TRAIL expression is consistently downregulated in HRAS(G12V)-transformed cells in stepwise tumorigenesis models derived from four different tissues due to DNA hypermethylation of CpG clusters within the TRAIL promoter. Decitabine de-silenced TRAIL, which remained inducible by interferon, while induction of TRAIL by blocking the HRAS(G12V)-activated mitogen-activated protein kinase pathway was subordinated to epigenetic silencing. Decitabine induced apoptosis through upregulation of endogenous TRAIL in cooperation with favorable regulation of key players acting in TRAIL-mediated apoptosis. Apoptosis induction by exogenously added TRAIL was largely increased by decitabine. In vivo treatment of xenografted human HRAS(G12V)-transformed human epithelial kidney or syngenic mice tumors by decitabine blocked tumor growth induced TRAIL expression and apoptosis. Our results emphasize the potential of decitabine to enhance TRAIL-induced apoptosis in tumors and thus provide a rationale for combination therapies with decitabine to increase tumor-selective apoptosis.
authors.affiliation: Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/Université de Strasbourg, 1 Rue Laurent Fries, BP 10142, IGBMC, 67404 Illkirch CEDEX, France.
authors.forename: Per
authors.initials: P
authors.lastname: Lund
authors.forename: Irina
authors.initials: I
authors.lastname: Kotova
authors.forename: Valérie
authors.initials: V
authors.lastname: Kedinger
authors.forename: Harshal
authors.initials: H
authors.lastname: Khanwalkar
authors.forename: Emilie
authors.initials: E
authors.lastname: Voltz
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D015536:Down-Regulation / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D007372:Interferons / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077209:Decitabine; D007372:Interferons; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D001374:Azacitidine