title: MicroRNA-16 mediates the regulation of a senescence-apoptosis switch in cutaneous T-cell and other non-Hodgkin lymphomas.
abstract: Multiple sequential genetic and epigenetic alterations underlie cancer development and progression. Overcoming cellular senescence is an early step in cancer pathogenesis. Here, we demonstrate that a noncoding regulatory RNA, microRNA-16 (miR-16), has the potential to induce cellular senescence. First, we examined the expression of miR-16 in primary cutaneous T-cell lymphoma (CTCL) and other non-Hodgkin T/natural killer (NK)-cell lymphomas and found that miR-16 was downregulated than that in the corresponding normal cells. Notably, miR-16 expression was reduced as the primary CTCL progressed from the early stage to the advanced stage. Next, we transduced CTCL cells with miR-16 to examine whether this miRNA exhibited tumor-suppressive effects in CTCL cells. In CTCL cells expressing wild-type p53, forced expression of miR-16 enhanced p21 expression via downregulation of the polycomb group protein Bmi1, thereby inducing cellular senescence. Alternatively, in CTCL cells lacking functional p53, miR-16 induced compensatory apoptosis. The miR-16 transfection significantly decreased senescent cells and increased apoptotic cells in p21-knockdown CTCL cells expressing wild-type p53, suggesting that the presence or absence of p21 may be the most important condition in the senescence-apoptosis switch in CTCL lymphomagenesis. Furthermore, we found that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) restored the expression of miR-16 and its essential targets, induced senescence in CTCL cells expressing wild-type p53 and promoted apoptosis in cells with nonfunctional p53. Moreover, we found that other T/NK-cell lymphoma cell lines showed similar tumor-suppressive effects in response to miR-16 and SAHA and that these effects were dependent on p53 status. These results suggested that epigenetic silencing of miR-16 may be a key step during lymphoma development. Elucidation of the essential targets of miR-16 and SAHA provides a basis for the clinical application of SAHA in the treatment of CTCL and other non-Hodgkin T/NK-cell lymphomas.
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kitadate
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Teshima
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Toyota
authors.affiliation: Department of Dermatology, Akita University, Akita, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Hasunuma
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Dermatology, University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Miyagaki
authors.affiliation: Department of Dermatology, University of Tokyo, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sugaya
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tagawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000077337:Vorinostat
chemical_list: C069077:BMI1 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077337:Vorinostat; D063150:Polycomb Repressive Complex 1