Wu Kaixin, Woo Seon Min, Kwon Taeg Kyu
Department of Immunology, School of Medicine, Keimyung University, Daegu, Korea.
J Cancer Prev. 2020 Jun 30;25(2):79-86. doi: 10.15430/JCP.2020.25.2.79.
Lysine-specific histone demethylase 1 (LSD1), also known as KDM1A, can remove the methyl group from lysine 4 and 9 at histone H3, which regulates transcriptional suppression and activation. Recently, high expression of LSD1 in tumors has been shown to be involved in cancer cell proliferation, metastasis, and poor prognosis. We found that SP2509, a potent and reversible inhibitor of LSD1, induced apoptosis in human renal carcinoma (Caki and ACHN) and glioma (U87MG) cells. Pharmacological inhibition and siRNA-mediated silencing of LSD1 expression effectively downregulated anti-apoptotic proteins such as Bcl-2 and Mcl-1. Ectopic expression of these proteins markedly attenuated SP2509-induced apoptosis. At a mechanistic level, we found that inhibition of LSD1 downregulated Bcl-2 at a transcriptional level. Interestingly, protein expression of Mcl-1 was modulated at a post-translation level. Our results reveal that LSD1 could induce apoptotic cell death in renal carcinoma cells through downregulation of Bcl-2 and Mcl-1.
赖氨酸特异性组蛋白去甲基化酶1（LSD1），也被称为KDM1A，能够去除组蛋白H3上赖氨酸4和9位点的甲基基团，从而调节转录抑制和激活。最近研究表明，LSD1在肿瘤中的高表达与癌细胞增殖、转移及不良预后有关。我们发现，SP2509，一种强效且可逆的LSD1抑制剂，可诱导人肾癌（Caki和ACHN）及胶质瘤（U87MG）细胞凋亡。LSD1的药理学抑制及siRNA介导的表达沉默有效下调了抗凋亡蛋白如Bcl-2和Mcl-1。这些蛋白的异位表达显著减弱了SP2509诱导的凋亡。在机制层面，我们发现抑制LSD1在转录水平下调了Bcl-2。有趣的是，Mcl-1的蛋白表达在翻译后水平受到调控。我们的结果表明，LSD1可通过下调Bcl-2和Mcl-1诱导肾癌细胞凋亡。
