Chemical inhibition of LSD1 leads to epithelial to mesenchymal transition in vitro of an oral squamous cell carcinoma OM-1 cell line via release from LSD1-dependent suppression of ZEB1
Chemical inhibition of LSD1 leads to epithelial to mesenchymal transition in vitro of an oral squamous cell carcinoma OM-1 cell line via release from LSD1-dependent suppression of ZEB1
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DOI：
10.1016/j.bbrc.2023.01.062
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发表时间：
2023-01-27
影响因子：
3.1
通讯作者：
Aikawa，Tomonao
中科院分区：
文献类型：
--
作者：
Yamakado，Nao;Okuda，Satoshi;Aikawa，Tomonao
基因表达的表观遗传调控决定了细胞的可塑性。口腔鳞状细胞癌（SCC）具有双向细胞可塑性，即上皮分化和上皮间质转化（EMT）。表观遗传调节剂LSD 1是一种组蛋白H3特异性脱甲基酶，其活性的化学抑制剂已被开发为抗癌治疗剂。口腔鳞状细胞癌细胞系OM-1的双向可塑性已被表征，但仍不清楚化学LSD 1抑制剂如何影响细胞可塑性。在这里，我们报告了对癌症治疗的不利影响，这是EMT诱导体外的化学LSD 1抑制剂。LSD 1抑制剂导致OM-1中的EMT-TF ZEB 1发生EMT。此外，OM-1中另外的EMT-TF蜗牛依赖性部分EMT表型与LSD 1依赖性ZEB 1诱导一起进展为完全EMT。在LSD 1抑制下，ZEB 1的启动子活性上调。ZEB 1的调控染色质区域在LSD 1的化学抑制下积累组蛋白H3甲基化。LSD 1抑制剂也在体外上调上皮基因表达;然而，在癌症治疗中应考虑LSD 1抑制剂的双向作用。
The epigenetic regulation for gene expression determines cell plasticity. Oral squamous cell carcinoma (SCC) exhibits bidirectional cell plasticity, ie epithelial differentiation and epithelial to mesenchymal transition (EMT). The epigenetic regulator LSD1 is a histone H3-specific demethylase to which chemical inhibitors for its activity had been developed as an anti-cancer therapeutics. The bidirectional plasticity of the oral SCC cell line OM-1 had been characterized, but it remained unclear how chemical LSD1 inhibitors affect cell plasticity. Here we reported an adverse effect against cancer therapeutics, which was EMT induction in vitro by the chemical LSD1 inhibitor. The LSD1 inhibitor caused EMT-TF ZEB1 in OM-1 to undergo EMT. Furthermore, an additional EMT-TF Snail-dependent partial EMT phenotype in OM-1 progressed to complete EMT in conjunction with LSD1 inhibitor-dependent ZEB1 induction. The promotor activity of ZEB1 was up-regulated under LSD1 inhibition. The regulatory chromatin regions of ZEB1 accumulated histone H3 methylation under the chemical inhibition of LSD1. The LSD1 inhibitor also upregulates epithelial gene expression in vitro; however, the bidirectional effect of LSD1 inhibitor should be considered in cancer therapeutics.