title: Melatonin regulates PARP1 to control the senescence-associated secretory phenotype (SASP) in human fetal lung fibroblast cells.
abstract: Cellular senescence is an important tumor-suppressive mechanism. However, acquisition of a senescence-associated secretory phenotype (SASP) in senescent cells has deleterious effects on the tissue microenvironment and, paradoxically, promotes tumor progression. In a drug screen, we identified melatonin as a novel SASP suppressor in human cells. Strikingly, melatonin blunts global SASP gene expression upon oncogene-induced senescence (OIS). Moreover, poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, was identified as a new melatonin-dependent regulator of SASP gene induction upon OIS. Here, we report two different but potentially coherent epigenetic strategies for melatonin regulation of SASP. The interaction between the telomeric repeat-containing RNA (TERRA) and PARP-1 stimulates the SASP, which was attenuated by 67.9% (illustrated by the case of IL8) by treatment with melatonin. Through binding to macroH2A1.1, PARP-1 recruits CREB-binding protein (CBP) to mediate acetylation of H2BK120, which positively regulates the expression of target SASP genes, and this process is interrupted by melatonin. Consequently, the findings provide novel insight into melatonin's epigenetic role via modulating PARP-1 in suppression of SASP gene expression in OIS-induced senescent cells. Our studies identify melatonin as a novel anti-SASP molecule, define PARP-1 as a new target by which melatonin regulates SASP, and establish a new epigenetic paradigm for a pharmacological mechanism by which melatonin interrupts PARP-1 interaction with the telomeric long noncoding RNA(lncRNA) or chromatin.
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Songtao
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiaojiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Peiliang
authors.initials: P
authors.lastname: Geng
authors.affiliation: Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Lisha
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Ruan
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jianfang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Ganfeng
authors.initials: G
authors.lastname: Xie
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Ou
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xueli
authors.initials: X
authors.lastname: Pang
authors.affiliation: Department of Biochemistry and Molecular Biology, The Third Military Medical University, Chongqing, China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Miao
authors.affiliation: Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China.
authors.forename: Hongshan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Houjie
authors.identifier: http://orcid.org/0000-0002-4755-9341
authors.initials: H
authors.lastname: Liang
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology; D008550:Melatonin / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D008550:Melatonin
keywords: 
  SASP
  ; 
  TERRA
  ; PARP1; cellular senescence; histone acetylation; melatonin