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Melatonin regulates PARP 1 to control the senescence‐associated secretory phenotype ( SASP ) in human fetal lung fibroblast cells
Author(s) -
Yu Songtao,
Wang Xiaojiao,
Geng Peiliang,
Tang Xudong,
Xiang Lisha,
Lu Xin,
Li Jianjun,
Ruan Zhihua,
Chen Jianfang,
Xie Ganfeng,
Wang Zhe,
Ou Juanjuan,
Peng Yuan,
Luo Xi,
Zhang Xuan,
Dong Yan,
Pang Xueli,
Miao Hongming,
Chen Hongshan,
Liang Houjie
Publication year - 2017
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12405
Subject(s) - melatonin , biology , epigenetics , senescence , microbiology and biotechnology , poly adp ribose polymerase , regulation of gene expression , chromatin immunoprecipitation , cancer research , gene expression , promoter , gene , endocrinology , polymerase , genetics
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 IL 8) by treatment with melatonin. Through binding to macroH2A1.1, PARP ‐1 recruits CREB ‐binding protein ( CBP ) to mediate acetylation of H2 BK 120, 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 (lnc RNA ) or chromatin.