Genome, Cell, and Developmental Biology, Department of Biology, Indiana University Bloomington, Bloomington, Indiana.
Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana.
Mol Cancer Res. 2020 Feb;18(2):264-277. doi: 10.1158/1541-7786.MCR-19-0748. Epub 2019 Nov 8.
Activation of the epithelial-to-mesenchymal transition (EMT) program is a critical mechanism for initiating cancer progression and migration. Colorectal cancers contain many genetic and epigenetic alterations that can contribute to EMT. Mutations activating the PI3K/AKT signaling pathway are observed in >40% of patients with colorectal cancer contributing to increased invasion and metastasis. Little is known about how oncogenic signaling pathways such as PI3K/AKT synergize with chromatin modifiers to activate the EMT program. Lysine-specific demethylase 1 (LSD1) is a chromatin-modifying enzyme that is overexpressed in colorectal cancer and enhances cell migration. In this study, we determine that LSD1 expression is significantly elevated in patients with colorectal cancer with mutation of the catalytic subunit of PI3K, , compared with patients with colorectal cancer with WT . LSD1 enhances activation of the AKT kinase in colorectal cancer cells through a noncatalytic mechanism, acting as a scaffolding protein for the transcription-repressing CoREST complex. In addition, growth of -mutant colorectal cancer cells is uniquely dependent on LSD1. Knockdown or CRISPR knockout of LSD1 blocks AKT-mediated stabilization of the EMT-promoting transcription factor Snail and effectively blocks AKT-mediated EMT and migration. Overall, we uniquely demonstrate that LSD1 mediates AKT activation in response to growth factors and oxidative stress, and LSD1-regulated AKT activity promotes EMT-like characteristics in a subset of -mutant cells. IMPLICATIONS: Our data support the hypothesis that inhibitors targeting the CoREST complex may be clinically effective in patients with colorectal cancer harboring mutations.
上皮-间充质转化 (EMT) 程序的激活是启动癌症进展和迁移的关键机制。结直肠癌含有许多可导致 EMT 的遗传和表观遗传改变。在 >40%的结直肠癌患者中观察到激活 PI3K/AKT 信号通路的突变，导致侵袭和转移增加。关于致癌信号通路（如 PI3K/AKT）如何与染色质修饰物协同激活 EMT 程序，目前知之甚少。赖氨酸特异性去甲基酶 1 (LSD1) 是一种染色质修饰酶，在结直肠癌中过度表达，增强细胞迁移。在这项研究中，我们确定与结直肠癌中 WT 相比，PI3K 催化亚基突变的结直肠癌患者 LSD1 表达显著升高。LSD1 通过非催化机制增强结直肠癌细胞中 AKT 激酶的激活，作为转录抑制 CoREST 复合物的支架蛋白。此外，-突变结直肠癌细胞的生长独特地依赖于 LSD1。LSD1 的敲低或 CRISPR 敲除阻断了 AKT 介导的 EMT 促进转录因子 Snail 的稳定，并有效阻断了 AKT 介导的 EMT 和迁移。总的来说，我们独特地证明了 LSD1 介导 AKT 激活以响应生长因子和氧化应激，并且 LSD1 调节的 AKT 活性在一组 -突变细胞中促进 EMT 样特征。意义：我们的数据支持这样一种假设，即针对 CoREST 复合物的抑制剂可能对携带 突变的结直肠癌患者具有临床疗效。
