title: Classical NF-κB pathway is responsible for APOBEC3B expression in cancer cells.
abstract: APOBEC3B (A3B) is a DNA cytosine deaminase and catalyzes cytosine deamination, resulting in mutations in genomic DNA. A3B is aberrantly expressed in a variety of cancers and considered to be a source of genomic mutations that contribute to cancer progression and metastasis. However, the mechanisms through which A3B expression is dysregulated in cancer cells are not fully elucidated. Here we report that the classical NF-κB pathway plays a crucial role in the transcriptional regulation of A3B in various cancer cells, including lymphoid malignancies. PMA, a strong activator of PKC, induces A3B at both mRNA and protein levels in cancer cell lines, and specific inhibitors of both PKC and IKK downregulate A3B expression. Using luciferase reporter and EMSA assays, we identify 3 NF-κΒ binding sites in the A3B promoter and reveal that NF-κB p65/p50 and p65/c-Rel heterodimers are important for A3B transcription. These results suggest that the classical NF-κB pathway is responsible for activation of A3B mRNA expression and further imply that inhibition of PKC and IKK might augment cancer treatment by reducing cancer progression and metastasis through downregulation of A3B expression.
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Wataru
authors: W
authors: Maruyama
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Kotaro
authors: K
authors: Shirakawa
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Hiroyuki
authors: H
authors: Matsui
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Tadahiko
authors: T
authors: Matsumoto
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Hiroyuki
authors: H
authors: Yamazaki
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Anamaria D
authors: AD
authors: Sarca
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Yasuhiro
authors: Y
authors: Kazuma
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Masayuki
authors: M
authors: Kobayashi
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Keisuke
authors: K
authors: Shindo
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: atakaori@kuhp.kyoto-u.ac.jp.
authors: Akifumi
authors: A
authors: Takaori-Kondo
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D015778:Minor Histocompatibility Antigens / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D012333:RNA, Messenger; D011493:Protein Kinase C; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase; D013755:Tetradecanoylphorbol Acetate
keywords: APOBEC3B; IκB kinase (IKK); NF-kappa B (NF-κB); Phorbol myristate acetate (PMA); Protein kinase C (PKC)