title: Lysine-specific demethylase 2B (KDM2B)-let-7-enhancer of zester homolog 2 (EZH2) pathway regulates cell cycle progression and senescence in primary cells.
abstract: Sustained expression of the histone demethylase, KDM2B (Ndy1/FBXL10/JHDM1B), bypasses cellular senescence in primary mouse embryonic fibroblasts (MEFs). Here, we show that KDM2B is a conserved regulator of lifespan in multiple primary cell types and defines a program in which this chromatin-modifying enzyme counteracts the senescence-associated down-regulation of the EZH2 histone methyltransferase. Senescence in MEFs epigenetically silences KDM2B and induces the tumor suppressor miRNAs let-7b and miR-101, which target EZH2. Forced expression of KDM2B promotes immortalization by silencing these miRNAs through locus-specific histone H3 K36me2 demethylation, leading to EZH2 up-regulation. Overexpression of let-7b down-regulates EZH2, induces premature senescence, and counteracts immortalization of MEFs driven by KDM2B. The KDM2B-let-7-EZH2 pathway also contributes to the proliferation of immortal Ink4a/Arf null fibroblasts suggesting that, beyond its anti-senescence role in primary cells, this histone-modifying enzyme functions more broadly in the regulation of cellular proliferation.
authors.affiliation: Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. atzatsos@partners.org
authors.forename: Alexandros
authors.initials: A
authors.lastname: Tzatsos
authors.forename: Polina
authors.initials: P
authors.lastname: Paskaleva
authors.forename: Stephania
authors.initials: S
authors.lastname: Lymperi
authors.forename: Gianmarco
authors.initials: G
authors.lastname: Contino
authors.forename: Svetlana
authors.initials: S
authors.lastname: Stoykova
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D017124:Conserved Sequence / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D044783:F-Box Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2; D015398:Signal Transduction; D013379:Substrate Specificity; D015854:Up-Regulation / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D044783:F-Box Proteins; D035683:MicroRNAs; C542687:mirnlet7 microRNA, mouse; D056484:Jumonji Domain-Containing Histone Demethylases; C524747:Kdm2b protein, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D020727:ADP-Ribosylation Factors; D008239:Lysine