Epigenetic Inactivation of the Circadian Clock Gene <i>BMAL1</i> in Hematologic Malignancies
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- Hiroaki Taniguchi
- 1Cancer Epigenetics and Biology Program and 2Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet, and 3Institució Catalana de Recerca i Estudis Avançats, Catalonia, Spain; and 4First Department of Internal Medicine, Sapporo Medical University School of Medicine and 5Sapporo Medical University, Sapporo, Japan
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- Agustin F. Fernández
- 1Cancer Epigenetics and Biology Program and 2Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet, and 3Institució Catalana de Recerca i Estudis Avançats, Catalonia, Spain; and 4First Department of Internal Medicine, Sapporo Medical University School of Medicine and 5Sapporo Medical University, Sapporo, Japan
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- Fernando Setién
- 1Cancer Epigenetics and Biology Program and 2Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet, and 3Institució Catalana de Recerca i Estudis Avançats, Catalonia, Spain; and 4First Department of Internal Medicine, Sapporo Medical University School of Medicine and 5Sapporo Medical University, Sapporo, Japan
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- Santiago Ropero
- 1Cancer Epigenetics and Biology Program and 2Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet, and 3Institució Catalana de Recerca i Estudis Avançats, Catalonia, Spain; and 4First Department of Internal Medicine, Sapporo Medical University School of Medicine and 5Sapporo Medical University, Sapporo, Japan
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- Esteban Ballestar
- 1Cancer Epigenetics and Biology Program and 2Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet, and 3Institució Catalana de Recerca i Estudis Avançats, Catalonia, Spain; and 4First Department of Internal Medicine, Sapporo Medical University School of Medicine and 5Sapporo Medical University, Sapporo, Japan
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- Alberto Villanueva
- 1Cancer Epigenetics and Biology Program and 2Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet, and 3Institució Catalana de Recerca i Estudis Avançats, Catalonia, Spain; and 4First Department of Internal Medicine, Sapporo Medical University School of Medicine and 5Sapporo Medical University, Sapporo, Japan
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- Hiroyuki Yamamoto
- 1Cancer Epigenetics and Biology Program and 2Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet, and 3Institució Catalana de Recerca i Estudis Avançats, Catalonia, Spain; and 4First Department of Internal Medicine, Sapporo Medical University School of Medicine and 5Sapporo Medical University, Sapporo, Japan
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- Kohzoh Imai
- 1Cancer Epigenetics and Biology Program and 2Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet, and 3Institució Catalana de Recerca i Estudis Avançats, Catalonia, Spain; and 4First Department of Internal Medicine, Sapporo Medical University School of Medicine and 5Sapporo Medical University, Sapporo, Japan
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- Yasuhisa Shinomura
- 1Cancer Epigenetics and Biology Program and 2Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet, and 3Institució Catalana de Recerca i Estudis Avançats, Catalonia, Spain; and 4First Department of Internal Medicine, Sapporo Medical University School of Medicine and 5Sapporo Medical University, Sapporo, Japan
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- Manel Esteller
- 1Cancer Epigenetics and Biology Program and 2Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet, and 3Institució Catalana de Recerca i Estudis Avançats, Catalonia, Spain; and 4First Department of Internal Medicine, Sapporo Medical University School of Medicine and 5Sapporo Medical University, Sapporo, Japan
抄録
<jats:title>Abstract</jats:title> <jats:p>Disruption of circadian rhythms, daily oscillations in biological processes that are regulated by an endogenous clock, has been linked to tumorigenesis. Normal and malignant tissues often show asynchronies in cell proliferation and metabolic rhythms. Cancer chronotherapy takes biological time into account to improve the therapy. However, alterations of the circadian clock machinery genes have rarely been reported in human cancer. Herein, we show that the BMAL1 gene, a core component of the circadian clock, is transcriptionally silenced by promoter CpG island hypermethylation in hematologic malignancies, such as diffuse large B-cell lymphoma and acute lymphocytic and myeloid leukemias. We also describe how BMAL1 reintroduction in hypermethylated leukemia/lymphoma cells causes growth inhibition in colony assays and nude mice, whereas BMAL1 depletion by RNA interference in unmethylated cells enhances tumor growth. We also show that BMAL1 epigenetic inactivation impairs the characteristic circadian clock expression pattern of genes such as C-MYC, catalase, and p300 in association with a loss of BMAL1 occupancy in their respective promoters. Furthermore, the DNA hypermethylation–associated loss of BMAL1 also prevents the recruitment of its natural partner, the CLOCK protein, to their common targets, further enhancing the perturbed circadian rhythm of the malignant cells. These findings suggest that BMAL1 epigenetic inactivation contributes to the development of hematologic malignancies by disrupting the cellular circadian clock. [Cancer Res 2009;69(21):8447–54]</jats:p>
収録刊行物
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- Cancer Research
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Cancer Research 69 (21), 8447-8454, 2009-10-28
American Association for Cancer Research (AACR)
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キーワード
詳細情報 詳細情報について
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- CRID
- 1362262943385483520
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- ISSN
- 15387445
- 00085472
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- データソース種別
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- Crossref