title: Immunomodulatory drugs act as inhibitors of DNA methyltransferases and induce PU.1 up-regulation in myeloma cells.
abstract: Immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide are efficacious in the treatment of multiple myeloma and significantly prolong their survival. However, the mechanisms of such effects of IMiDs have not been fully elucidated. Recently, cereblon has been identified as a target binding protein of thalidomide. Lenalidomide-resistant myeloma cell lines often lose the expression of cereblon, suggesting that IMiDs act as an anti-myeloma agent through interacting with cereblon. Cereblon binds to damaged DNA-binding protein and functions as a ubiquitin ligase, inducing degradation of IKZF1 and IKZF3 that are essential transcription factors for B and T cell development. Degradation of both IKZF1 and IKZF3 reportedly suppresses myeloma cell growth. Here, we found that IMiDs act as inhibitors of DNA methyltransferases (DMNTs). We previously reported that PU.1, which is an ETS family transcription factor and essential for myeloid and lymphoid development, functions as a tumor suppressor in myeloma cells. PU.1 induces growth arrest and apoptosis of myeloma cell lines. In this study, we found that low-dose lenalidomide and pomalidomide up-regulate PU.1 expression through inducing demethylation of the PU.1 promoter. In addition, IMiDs inhibited DNMT1, DNMT3a, and DNMT3b activities in vitro. Furthermore, lenalidomide and pomalidomide decreased the methylation status of the whole genome in myeloma cells. Collectively, IMiDs exert demethylation activity through inhibiting DNMT1, 3a, and 3b, and up-regulating PU.1 expression, which may be one of the mechanisms of the anti-myeloma activity of IMiDs.
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Endo
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amano
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Nishimura
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Niina
authors.initials: N
authors.lastname: Ueno
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Shikiko
authors.initials: S
authors.lastname: Ueno
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yuki
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Fujiwara
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Wada
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Hirata
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hata
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
authors.affiliation: Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan. Electronic address: yokuno@gpo.kumamoto-u.ac.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Okuno
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D007155:Immunologic Factors; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1
keywords: DNA methyltransferase; Lenalidomide; Multiple myeloma; PU.1; Pomalidomide