Yamakado Nao, Okuda Satoshi, Tobiume Kei, Uetsuki Ryo, Ono Shigehiro, Mizuta Kuniko, Nakagawa Takayuki, Aikawa Tomonao
Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Biochem Biophys Res Commun. 2023 Mar 5;647:23-29. doi: 10.1016/j.bbrc.2023.01.062. Epub 2023 Jan 25.
The epigenetic regulation for gene expression determines cell plasticity. Oral squamous cell carcinoma (SCC) exhibits bidirectional cell plasticity, i.e. 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.
基因表达的表观遗传调控决定细胞可塑性。口腔鳞状细胞癌（SCC）表现出双向细胞可塑性，即上皮分化和上皮-间质转化（EMT）。表观遗传调节因子LSD1是一种组蛋白H3特异性去甲基化酶，针对其活性的化学抑制剂已被开发用作抗癌治疗药物。口腔SCC细胞系OM-1的双向可塑性已得到表征，但尚不清楚化学LSD1抑制剂如何影响细胞可塑性。在此，我们报道了一种抗癌治疗的不良反应，即化学LSD1抑制剂在体外诱导EMT。LSD1抑制剂导致OM-1中的EMT转录因子ZEB1发生EMT。此外，OM-1中一种额外的依赖EMT转录因子Snail的部分EMT表型，与依赖LSD1抑制剂的ZEB1诱导一起进展为完全EMT。在LSD1抑制下，ZEB1的启动子活性上调。在LSD1的化学抑制下，ZEB1的调控染色质区域积累了组蛋白H3甲基化。LSD1抑制剂在体外也上调上皮基因表达；然而，在癌症治疗中应考虑LSD1抑制剂的双向作用。
