title: Polycomb-mediated loss of miR-31 activates NIK-dependent NF-κB pathway in adult T cell leukemia and other cancers.
abstract: Constitutive NF-κB activation has causative roles in adult T cell leukemia (ATL) caused by HTLV-1 and other cancers. Here, we report a pathway involving Polycomb-mediated miRNA silencing and NF-κB activation. We determine the miRNA signatures and reveal miR-31 loss in primary ATL cells. MiR-31 negatively regulates the noncanonical NF-κB pathway by targeting NF-κB inducing kinase (NIK). Loss of miR-31 therefore triggers oncogenic signaling. In ATL cells, miR-31 level is epigenetically regulated, and aberrant upregulation of Polycomb proteins contribute to miR-31 downregulation in an epigenetic fashion, leading to activation of NF-κB and apoptosis resistance. Furthermore, this emerging circuit operates in other cancers and receptor-initiated NF-κB cascade. Our findings provide a perspective involving the epigenetic program, inflammatory responses, and oncogenic signaling.
authors.affiliation: Graduate School of Frontier Sciences, The University of Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamagishi
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nakano
authors.forename: Ariko
authors.initials: A
authors.lastname: Miyake
authors.forename: Tadanori
authors.initials: T
authors.lastname: Yamochi
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Kagami
authors.forename: Akihisa
authors.initials: A
authors.lastname: Tsutsumi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Matsuda
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.forename: Satsuki
authors.initials: S
authors.lastname: Muto
authors.forename: Atae
authors.initials: A
authors.lastname: Utsunomiya
authors.forename: Kazunari
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Uchimaru
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D063146:Polycomb-Group Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D035683:MicroRNAs; D016328:NF-kappa B; D063146:Polycomb-Group Proteins; D017346:Protein Serine-Threonine Kinases; D012097:Repressor Proteins; D000097782:NF-kappaB-Inducing Kinase; C534612:MIRN31 microRNA, human