FOXQ1 regulates senescence-associated inflammation via activation of SIRT1 expression.
FOXQ1 regulates senescence-associated inflammation via activation of SIRT1 expression.
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FOXQ1 通过激活 SIRT1 表达调节衰老相关炎症
DOI：
10.1038/cddis.2017.340
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发表时间：
2017-07-20
影响因子：
9
通讯作者：
Hong T
中科院分区：
文献类型：
--
作者：
Wang P;Lv C;Zhang T;Liu J;Yang J;Guan F;Hong T
细胞衰老是阻止癌前细胞增殖的肿瘤发展的初始屏障。然而，衰老细胞的一些特征似乎通过衰老相关分泌表型（SASP）促进肿瘤进展。在这里，我们证明了叉头盒Q1（FOXQ 1）的蛋白水平在多种肿瘤中高度过表达，在复制和癌基因诱导的衰老过程中显着下调。此外，FOXQ 1的过表达会延迟衰老，而FOXQ 1的沉默会导致人成纤维细胞过早衰老。此外，我们确定FOXQ 1通过直接结合SIRT 1启动子进行转录调节来上调SIRT 1表达。FOXQ 1通过调节SIRT 1-NF-κB通路，抑制炎症细胞因子IL-6和IL-8的表达，从而显著抑制复制性衰老。此外，FOXQ 1在人食管癌细胞中的过表达和FOXQ 1的消融抑制了食管癌细胞（EC 109和EC 9706）在小鼠异种移植模型中的体内致瘤能力。综上所述，这些发现揭示了FOXQ 1同时调节SASP和肿瘤发展的先前未确定的作用。
Cellular senescence is an initial barrier to tumor development that prevents the proliferation of premalignant cells. However, some of the features of senescent cells seem to promote tumor progression via senescence-associated secretory phenotype (SASP). Here, we demonstrated that the protein level of forkhead box Q1 (FOXQ1), which highly overexpresses in several kinds of tumors, was significantly downregulated during both replicative and oncogene-induced senescence. Moreover, overexpression of FOXQ1 delayed senescence, whereas FOXQ1 silence led to premature senescence in human fibroblasts. Furthermore, we identified that FOXQ1 upregulated SIRT1 expression through transcriptional regulation via directly binding to the SIRT1 promoter. Finally, we showed that FOXQ1 remarkably inhibited the replicative senescence through depressing the expression of the inflammatory cytokines interleukin-6 (IL-6) and IL-8 via modulation of SIRT1-NF-κB pathway. In addition, FOXQ1 overexpressed in human esophageal cancer cells and ablation of FOXQ1 restrained the tumourigenic ability of the esophageal cancer cells (EC109 and EC9706) in a mouse xenograft model in vivo. Taken together, these findings uncover a previously unidentified role of FOXQ1 regulating SASP and tumor development at same time.
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