Hino Shinjiro, Kohrogi Kensaku, Nakao Mitsuyoshi
Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development, Tokyo, Japan.
Cancer Sci. 2016 Sep;107(9):1187-92. doi: 10.1111/cas.13004. Epub 2016 Sep 1.
Epigenetic mechanisms underlie the phenotypic plasticity of cells, while aberrant epigenetic regulation through genetic mutations and/or misregulated expression of epigenetic factors leads to aberrant cell fate determination, which provides a foundation for oncogenic transformation. Lysine-specific demethylase-1 (LSD1, KDM1A) removes methyl groups from methylated proteins, including histone H3, and is frequently overexpressed in various types of solid tumors and hematopoietic neoplasms. While LSD1 is involved in a wide variety of normal physiological processes, including stem cell maintenance and differentiation, it is also a key player in oncogenic processes, including compromised differentiation, enhanced cell motility and metabolic reprogramming. Here, we present an overview of how LSD1 epigenetically regulates cellular plasticity through distinct molecular mechanisms in different biological contexts. Targeted inhibition of the context-dependent activities of LSD1 may provide a highly selective means to eliminate cancer cells.
表观遗传机制是细胞表型可塑性的基础，而通过基因突变和/或表观遗传因子表达失调导致的异常表观遗传调控会导致异常的细胞命运决定，这为致癌转化奠定了基础。赖氨酸特异性去甲基化酶-1（LSD1，KDM1A）可从包括组蛋白H3在内的甲基化蛋白质上去除甲基基团，并且在各种实体瘤和造血肿瘤中经常过度表达。虽然LSD1参与多种正常生理过程，包括干细胞维持和分化，但它也是致癌过程中的关键因素，包括分化受损、细胞运动性增强和代谢重编程。在这里，我们概述了LSD1如何在不同生物学背景下通过独特的分子机制对细胞可塑性进行表观遗传调控。对LSD1的上下文依赖性活性进行靶向抑制可能提供一种高度选择性的方法来消除癌细胞。
