Chaetocin induces endoplasmic reticulum stress response and leads to death receptor 5-dependent apoptosis in human non-small cell lung cancer cells
Chaetocin induces endoplasmic reticulum stress response and leads to death receptor 5-dependent apoptosis in human non-small cell lung cancer cells
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DOI：
10.1007/s10495-015-1167-4
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发表时间：
2015-11-01
期刊：
影响因子：
7.2
通讯作者：
Su, Ling
中科院分区：
文献类型：
--
作者：
Liu, Xianfang;Guo, Sen;Su, Ling
表观遗传学异常与非小细胞肺癌的发生和发展有关。表观遗传药物正在研究和临床试验中。然而，表观遗传剂诱导细胞凋亡的分子机制尚不清楚。SUV39H1是组蛋白H3上赖氨酸9的重要甲基转移酶，通常与基因转录抑制有关，而角毛菌素是SUV39H1的抑制因子。在此，我们证明了毛壳素通过以依赖死亡受体5(DR5)的方式诱导细胞凋亡，有效地抑制了多个肺癌细胞的生长。毛壳素处理激活了内质网应激，导致ATF3和CHOP表达上调。此外，ATF3和CHOP参与了DR5的诱导和随后的细胞凋亡。当用siRNA沉默SUV39H1时，ATF3、CHOP和DR5的表达增加。此后，SUV39H1基因的敲除诱导了NSCLC细胞的凋亡。综上所述，毛壳素在药理上抑制了引发内质网应激的SUV39H1的活性，导致ATF3和CHOP的上调，最终导致DR5依赖的细胞凋亡。这些发现为表观遗传药物作为非小细胞肺癌新的治疗方法的抗肿瘤活性提供了新的解释。
Epigenetic abnormalities are associated with non-small cell lung cancer (NSCLC) initiation and progression. Epigenetic drugs are being studied and in clinical trials. However, the molecular mechanism underlying the apoptosis by the epigenetic agents remains unclear. SUV39H1 is an important methyl-transferase for lysine 9 on histone H3 and usually related to gene transcriptional suppression, and chaetocin acts as the inhibitor of SUV39H1. We demonstrated here that chaetocin effectively suppressed the growth of multiple lung cancer cells through inducing apoptosis in a death receptor 5 (DR5)-dependent manner. Chaetocin treatment activated endoplasmic reticulum (ER) stress which gave rise to the up-regulation of ATF3 and CHOP. Furthermore, ATF3 and CHOP contributed to the induction of DR5 and subsequent apoptosis. When SUV39H1 was silenced with siRNA, the expression of ATF3, CHOP and DR5 was elevated. Thereafter, knockdown of SUV39H1 induced apoptosis in NSCLC cells. In summary, chaetocin pharmacologically inhibits the activity of SUV39H1 which provokes ER stress and results in up-regulation of ATF3 and CHOP, leading to DR5-dependent apoptosis eventually. These findings provide a novel interpretation on the anti-neoplastic activity of epigenetic drugs as a new therapeutic approach in NSCLC.