title: MLL1 is essential for the senescence-associated secretory phenotype.
abstract: Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces "SASP-like" inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression.
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA; Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Brian C
authors.initials: BC
authors.lastname: Capell
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Adam M
authors.initials: AM
authors.lastname: Drake
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Jiajun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Parisha P
authors.initials: PP
authors.lastname: Shah
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Zhixun
authors.initials: Z
authors.lastname: Dou
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Jean
authors.initials: J
authors.lastname: Dorsey
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Simola
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Greg
authors.initials: G
authors.lastname: Donahue
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Morgan
authors.initials: M
authors.lastname: Sammons
authors.affiliation: Institute of Cancer Sciences, Beatson Laboratories, University of Glasgow, Glasgow G611BD, United Kingdom; Institute of Biomedical and Environmental Health Research, University of the West of Scotland, Paisley PA12BE, United Kingdom.
authors.forename: Taranjit Singh
authors.initials: TS
authors.lastname: Rai
authors.affiliation: Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Christopher
authors.initials: C
authors.lastname: Natale
authors.affiliation: Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Todd W
authors.initials: TW
authors.lastname: Ridky
authors.affiliation: Institute of Cancer Sciences, Beatson Laboratories, University of Glasgow, Glasgow G611BD, United Kingdom;
authors.forename: Peter D
authors.initials: PD
authors.lastname: Adams
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics*; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics; D061986:MCF-7 Cells; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000503:physiopathology; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C497422:KMT2A protein, human; D016328:NF-kappa B; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: DNA damage response; MLL1; epigenetic; inflammation; oncogene-induced senescence; senescence-associated secretory phenotype
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