Inhibition of H3K4 demethylation induces autophagy in cancer cell lines
Inhibition of H3K4 demethylation induces autophagy in cancer cell lines
复制标题
抑制 H3K4 去甲基化可诱导癌细胞系自噬
DOI：
10.1016/j.bbamcr.2017.08.005
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发表时间：
2017-12-01
影响因子：
5.1
通讯作者：
Chen, Xuefeng
中科院分区：
文献类型：
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作者：
Wang, Zhen;Long, Qiao-Yun;Chen, Xuefeng
表观遗传因子和相关的小分子已经出现强烈参与自噬过程。在这里，我们报告，2-PCPA和GSK-LSD 1，两种抑制剂的组蛋白H3 K4去甲基化酶KDM 1A/LSD 1，诱导自噬在多种哺乳动物细胞系。这两种小分子诱导LC 3 II的积累、自噬体和自溶酶体的形成以及SQSTM 1/p62降解。2-PCPA处理通过细胞周期停滞抑制细胞增殖，但不诱导细胞死亡。外源性表达KDM 1A/LSD 1可降低2-PCPA诱导的自噬表型。2-PCPA诱导的自噬需要LC 3-II加工机制。但用siRNA去除BECN 1和ULK 1并不影响2-PCPA引发的LC 3-II积累。2-PCPA处理诱导了整体基因表达程序的改变，包括一系列自噬相关基因，如SQSTM 1/p62。总之，我们的数据表明，KDM 1A/LSD 1抑制剂通过影响自噬相关基因的表达并以BECN 1非依赖性方式诱导自噬。
Epigenetic factors and related small molecules have emerged to be strongly involved in autophagy process. Here we report that 2-PCPA and GSK-LSD1, two inhibitors of histone H3K4 demethylase KDM1A/LSD1, induce autophagy in multiple mammalian cell lines. The two small molecules induce accumulation of LC3II, formation of autophagosome and autolysosome, and SQSTMl/p62 degradation. 2-PCPA treatment inhibits cell proliferation through cell cycle arrest but does not inducing cell death. Exogenous expression of KDM1A/LSD1 impaired the autophagic phenotypes triggered by 2-PCPA. The autophagy induced by 2-PCPA requires LC3-II processing machinery. But depletion of BECN1 and ULK1 with siRNA did not affect the LC3-II accumulation triggered by 2-PCPA. 2-PCPA treatment induces the change of global gene expression program, including a series of autophagyrelated genes, such as SQSTMl/p62. Taken together, our data indicate that KDM1A/LSD1 inhibitors induce autophagy through affecting the expression of autophagy-related genes and in a BECN1-independent manner.