title: MOZ (MYST3, KAT6A) inhibits senescence via the INK4A-ARF pathway.
abstract: Cellular senescence is an important mechanism that restricts tumour growth. The Ink4a-Arf locus (also known as Cdkn2a), which encodes p16(INK4A) and p19(ARF), has a central role in inducing and maintaining senescence. Given the importance of cellular senescence in restraining tumour growth, great emphasis is being placed on the identification of novel factors that can modulate senescence. The MYST-family histone acetyltransferase MOZ (MYST3, KAT6A), first identified in recurrent translocations in acute myeloid leukaemia, has been implicated in both the promotion and inhibition of senescence. In this study, we investigate the role of MOZ in cellular senescence and show that MOZ is a potent inhibitor of senescence via the INK4A-ARF pathway. Primary mouse embryonic fibroblasts (MEFs) isolated from Moz-deficient embryos exhibit premature senescence, which was rescued on the Ink4a-Arf(-/-) background. Importantly, senescence resulting from the absence of MOZ was not accompanied by DNA damage, suggesting that MOZ acts independently of the DNA damage response. Consistent with the importance of senescence in cancer, expression profiling revealed that genes overexpressed in aggressive and highly proliferative cancers are expressed at low levels in Moz-deficient MEFs. We show that MOZ is required to maintain normal levels of histone 3 lysine 9 (H3K9) and H3K27 acetylation at the transcriptional start sites of at least four genes, Cdc6, Ezh2, E2f2 and Melk, and normal mRNA levels of these genes. CDC6, EZH2 and E2F2 are known inhibitors of the INK4A-ARF pathway. Using chromatin immunoprecipitation, we show that MOZ occupies the Cdc6, Ezh2 and Melk loci, thereby providing a direct link between MOZ, H3K9 and H3K27 acetylation, and normal transcriptional levels at these loci. This work establishes that MOZ is an upstream inhibitor of the INK4A-ARF pathway, and suggests that inhibiting MOZ may be one way to induce senescence in proliferative tumour cells.
authors.affiliation: Division of Development and Cancer, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: B N
authors.initials: BN
authors.lastname: Sheikh
authors.affiliation: Division of Bioinformatics, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Phipson
authors.affiliation: Division of Development and Cancer, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: F
authors.initials: F
authors.lastname: El-Saafin
authors.affiliation: Division of Development and Cancer, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: H K
authors.initials: HK
authors.lastname: Vanyai
authors.affiliation: Division of Development and Cancer, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: N L
authors.initials: NL
authors.lastname: Downer
authors.affiliation: Murdoch Children's Research Institute, Melbourne, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Bird
authors.affiliation: Division of Development and Cancer, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Kueh
authors.affiliation: Division of Development and Cancer, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: R E
authors.initials: RE
authors.lastname: May
authors.affiliation: Division of Bioinformatics, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Mathematics and Statistics, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: G K
authors.initials: GK
authors.lastname: Smyth
authors.affiliation: Division of Development and Cancer, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: A K
authors.initials: AK
authors.lastname: Voss
authors.affiliation: Division of Development and Cancer, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Thomas
mesh_terms: D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004249:DNA Damage; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D051548:Histone Acetyltransferases / Q000172:deficiency / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D051548:Histone Acetyltransferases; C511438:MOZ protein, mouse