Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China.
Department of Radiation Oncology, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China.
Cell Mol Life Sci. 2020 Sep;77(17):3341-3350. doi: 10.1007/s00018-020-03489-9. Epub 2020 Mar 19.
It is well-established that Lysine-specific demethylase 1 (LSD1, also known as KDM1A) roles as a lysine demethylase canonically acting on H3K4me1/2 and H3K9me1/2 for regulating gene expression. Though the discovery of non-histone substrates methylated by LSD1 has largely expanded the functions of LSD1 as a typical demethylase, recent groundbreaking studies unveiled its non-catalytic functions as a second life for this demethylase. We and others found that LSD1 is implicated in the interaction with a line of proteins to exhibit additional non-canonical functions in a demethylase-independent manner. Here, we present an integrated overview of these recent literatures charging LSD1 with unforeseen functions to re-evaluate and summarize its non-catalytic biological roles beyond the current understanding of its demethylase activity. Given LSD1 is reported to be ubiquitously overexpressed in a variety of tumors, it has been generally considered as an innovative target for cancer therapy. We anticipate that these non-canonical functions of LSD1 will arouse the consideration that extending the LSD1-based drug discovery to targeting LSD1 protein interactions non-catalytically, not only its demethylase activity, may be a novel strategy for cancer prevention.
赖氨酸特异性脱甲基酶 1（LSD1，也称为 KDM1A）作为一种赖氨酸脱甲基酶，其经典作用是作用于 H3K4me1/2 和 H3K9me1/2，以调节基因表达，这一点已得到充分证实。尽管 LSD1 对非组蛋白底物的甲基化作用的发现极大地扩展了 LSD1 作为典型的去甲基酶的功能，但最近的突破性研究揭示了其非催化功能作为该去甲基酶的第二个生命。我们和其他人发现，LSD1 与一系列蛋白质相互作用，以去甲基酶非依赖性的方式表现出额外的非经典功能。在这里，我们对这些最近的文献进行了综合概述，这些文献赋予 LSD1 以前未预料到的功能，以重新评估和总结 LSD1 的非催化生物学作用，超出了对其去甲基酶活性的现有理解。鉴于 LSD1 在多种肿瘤中普遍过表达，它通常被认为是癌症治疗的创新靶点。我们预计，LSD1 的这些非经典功能将引起人们的关注，即将 LSD1 为基础的药物发现扩展到非催化靶向 LSD1 蛋白相互作用，而不仅仅是其去甲基酶活性，可能是癌症预防的一种新策略。
