Suppression of p16 alleviates the senescence-associated secretory phenotype.
Suppression of p16 alleviates the senescence-associated secretory phenotype.
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DOI：
10.18632/aging.202640
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发表时间：
2021-02-06
期刊：
影响因子：
--
通讯作者：
Aird KM
中科院分区：
文献类型：
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作者：
Buj R;Leon KE;Anguelov MA;Aird KM
癌基因诱导的衰老(OIS)以细胞周期抑制因子p16表达增加为特征，导致细胞周期停滞。在这种情况下，p16的抑制会导致增殖、衰老旁路，并有助于肿瘤的发生。OIS细胞的特征还包括一组差异很大的因子的表达和分泌，统称为衰老相关分泌表型(SASP)。SASP既可以是有益的，也可以是有害的，并以高度依赖于背景的方式影响微环境。P16抑制与SASP之间的关系尚不清楚。在此，我们发现，在包括OIS和DNA损伤诱导的衰老在内的多种模型中，p16的敲除降低了SASP因子和促炎细胞因子IL6和CXCL8的表达。值得注意的是，这与衰老相关的细胞周期停滞无关。此外，癌细胞和患者样本中p16的低表达对应于SASP基因表达的降低，这表明这是p16表达缺失的普遍影响。综上所述，我们的数据表明p16调节SASP基因的表达，这对于理解p16如何调节衰老和肿瘤微环境具有重要意义。
Oncogene-induced senescence (OIS) is characterized by increased expression of the cell cycle inhibitor p16, leading to a hallmark cell cycle arrest. Suppression of p16 in this context drives proliferation, senescence bypass, and contributes to tumorigenesis. OIS cells are also characterized by the expression and secretion of a widely variable group of factors collectively termed the senescence-associated secretory phenotype (SASP). The SASP can be both beneficial and detrimental and affects the microenvironment in a highly context-dependent manner. The relationship between p16 suppression and the SASP remains unclear. Here, we show that knockdown of p16 decreases expression of the SASP factors and pro-inflammatory cytokines IL6 and CXCL8 in multiple models, including OIS and DNA damage-induced senescence. Notably, this is uncoupled from the senescence-associated cell cycle arrest. Moreover, low p16 expression in both cancer cell lines and patient samples correspond to decreased SASP gene expression, suggesting this is a universal effect of loss of p16 expression. Together, our data suggest that p16 regulates SASP gene expression, which has implications for understanding how p16 modulates both the senescent and tumor microenvironment.