title: 5-aza-2'-deoxycytidine-mediated c-myc Down-regulation triggers telomere-dependent senescence by regulating human telomerase reverse transcriptase in chronic myeloid leukemia.
abstract: Increased proliferation rates as well as resistance to apoptosis are considered major obstacles for the treatment of patients with chronic myelogenous leukemia (CML), thus highlighting the need for novel therapeutic approaches. Since senescence has been recognized as a physiological barrier against tumorigenesis, senescence-based therapy could represent a new strategy against CML. DNA demethylating agent 5-aza-2'-deoxycytidine (DAC) was reported to induce cellular senescence but underlying mechanisms remain to be elucidated. Here, we report that exposure to DAC triggers senescence in chronic leukemia cell lines as evidenced by increased senescence-associated β-galactosidase activity and lysosomal mass, accompanied by an up-regulation of cell cycle-related genes. We provide evidence that DAC is able to decrease telomere length, to reduce telomerase activity and to decrease human telomerase reverse transcriptase (hTERT) expression through decreased binding of c-myc to the hTERT promoter. Altogether, our results reveal the role of c-myc in telomere-dependent DAC-induced senescence and therefore provide new clues for improving chronic human leukemia treatments.
authors: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
authors: Cindy
authors: C
authors: Grandjenette
authors: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
authors: Michael
authors: M
authors: Schnekenburger
authors: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
authors: Tommy
authors: T
authors: Karius
authors: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
authors: Jenny
authors: J
authors: Ghelfi
authors: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
authors: Anthoula
authors: A
authors: Gaigneaux
authors: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
authors: Estelle
authors: E
authors: Henry
authors: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
authors: Mario
authors: M
authors: Dicato
authors: College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea. Electronic address: marcdiederich@snu.ac.kr.
authors: Marc
authors: M
authors: Diederich
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D004249:DNA Damage / Q000187:drug effects; D000077209:Decitabine; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D019098:Telomerase / Q000235:genetics*; D059506:Telomere Shortening; D014158:Transcription, Genetic
chemical_list: D000964:Antimetabolites, Antineoplastic; D018797:Cell Cycle Proteins; D016271:Proto-Oncogene Proteins c-myc; D000077209:Decitabine; C509186:TERT protein, human; D019098:Telomerase; D001374:Azacitidine