title: Myc represses miR-15a/miR-16-1 expression through recruitment of HDAC3 in mantle cell and other non-Hodgkin B-cell lymphomas.
abstract: Our recent study demonstrated miR-15a/16-1 downregulation in mantle cell lymphoma (MCL). Here, we investigated mechanisms of miR-15a/16-1 transcriptional repression and its epigenetic regulation by c-Myc and histone deacetylase (HDAC) in MCL. c-Myc expression was detected in MCL cell lines and in the primary MCL samples, and pri-miR-15a/16-1 mRNAs were significantly upregulated in Mino and Jeko-1 cells with c-Myc knockdown by small interfering RNAs (siRNAs). Our co-immunoprecipitation analysis showed that c-Myc interacted with HDAC3. Moreover, using chromatin immunoprecipitation, we demonstrated that both c-Myc and HDAC3 co-localized to the two promoters of the miR-15a/16-1 cluster gene, DLEU2, and inhibition of HDAC3 increased histone acetylation of the DLEU2 promoters. Luciferase reporter assay confirmed the dependence of Myc-mediated DLEU2 transcriptional repression on HDAC3. Treatment with the pan-HDAC inhibitor, suberoylanilide hydroxamic acid and HDAC3 siRNA resulted in increased miR-15a/16-1 expression. The regulatory mechanism of miR-15a/16-1 was further demonstrated in Burkitt lymphoma and Myc overexpressing cell lines. These findings highlight the role of HDAC3 in Myc-induced miR-15a/16-1 changes and reveal novel mechanisms for c-Myc-driven microRNA suppression and malignant transformation in aggressive B-cell malignancies.
authors: Department of Malignant Hematology, Molecular Oncology and Experimental Therapeutics Program, H Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA.|Department of Immunology, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
authors: X
authors: X
authors: Zhang
authors: Department of Malignant Hematology, Molecular Oncology and Experimental Therapeutics Program, H Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA.
authors: X
authors: X
authors: Chen
authors: Department of Malignant Hematology, Molecular Oncology and Experimental Therapeutics Program, H Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA.
authors: J
authors: J
authors: Lin
authors: Department of Malignant Hematology, Molecular Oncology and Experimental Therapeutics Program, H Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA.
authors: T
authors: T
authors: Lwin
authors: Department of Malignant Hematology, Molecular Oncology and Experimental Therapeutics Program, H Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA.
authors: G
authors: G
authors: Wright
authors: Department of Malignant Hematology, Molecular Oncology and Experimental Therapeutics Program, H Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA.
authors: L C
authors: LC
authors: Moscinski
authors: Department of Malignant Hematology, Molecular Oncology and Experimental Therapeutics Program, H Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA.
authors: W S
authors: WS
authors: Dalton
authors: Department of Malignant Hematology, Molecular Oncology and Experimental Therapeutics Program, H Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA.
authors: E
authors: E
authors: Seto
authors: Department of Malignant Hematology, Molecular Oncology and Experimental Therapeutics Program, H Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA.
authors: K
authors: K
authors: Wright
authors: Department of Malignant Hematology, Molecular Oncology and Experimental Therapeutics Program, H Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA.
authors: E
authors: E
authors: Sotomayor
authors: Department of Malignant Hematology, Molecular Oncology and Experimental Therapeutics Program, H Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA.
authors: J
authors: J
authors: Tao
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering / Q000378:metabolism; D014166:Transferases; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000077337:Vorinostat; D000099186:Histone Deacetylase 3
chemical_list: D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D006877:Hydroxamic Acids; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; D014166:Transferases; D025521:Tumor Suppressor Proteins; D000077337:Vorinostat; D000099186:Histone Deacetylase 3; C109420:DLEU2 lncRNA, human; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; C489427:MYC protein, human