Melatonin regulates PARP-1 to control the senescence-associatedsecretory phenotype (SASP) in human fetal lung fibroblast cells
Melatonin regulates PARP-1 to control the senescence-associatedsecretory phenotype (SASP) in human fetal lung fibroblast cells
复制标题
褪黑激素调节 PARP1 来控制人胎肺成纤维细胞的衰老相关分泌表型 (SASP)
DOI：
10.1111/jpi.12405
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发表时间：
2017
影响因子：
10.3
通讯作者：
Houjie Liang
中科院分区：
文献类型：
--
作者：
Songtao Yu;Xiaojiao Wang;Peiliang Geng;Xudong Tang;Lisha Xiang;Xin Lu;Jianjun Li;Zhihua Ruan;Jianfang Chen;Ganfeng Xie;Zhe Wang;Juanjuan Ou;Yuan Peng;Xi Luo;Xuan Zhang;Yan Dong;Hongshan chen;Houjie Liang
细胞衰老是一种重要的肿瘤抑制机制。然而，在衰老细胞中获得衰老相关的分泌表型(SASP)会对组织微环境产生有害影响，而且矛盾的是，它会促进肿瘤的进展。在药物筛选中，我们发现褪黑素是人类细胞中一种新的SASP抑制因子。值得注意的是，褪黑素在癌基因诱导的衰老(OIS)中抑制了SASP基因的整体表达。此外，DNA损伤感受器聚腺苷二磷酸核糖聚合酶-1(PARP-1)被鉴定为SASP基因诱导OIS的一种新的褪黑素依赖调节因子。在这里，我们报告了两种不同但可能一致的表观遗传策略来调控SASP的褪黑素。含有端粒重复序列的RNA(Terra)与PARP-1相互作用可刺激SASP，褪黑素可使SASP减弱67.9%(以IL8为例)。PARP-1通过与宏观的H_2A1.1结合，招募CREB结合蛋白(CBP)来介导H_2BK120的乙酰化，正向调节靶基因SASP的表达，这一过程被褪黑素阻断。因此，这些发现通过调节PARP-1抑制OIS诱导的衰老细胞中SASP基因的表达，为褪黑素的表观遗传学作用提供了新的见解。我们的研究确定褪黑素是一种新的抗SASP分子，将PARP-1定义为褪黑素调节SASP的新靶点，并为褪黑素阻断PARP-1与端粒长非编码RNA(LncRNA)或染色质的相互作用的药理机制建立了新的表观遗传学范式。
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.