结直肠癌中组蛋白赖氨酸特异性去甲基化酶1协同因子的研究进展

Progress of synergistic factors of histone lysine specific demethylase 1 in colorectal cancer

结直肠癌细胞中组蛋白赖氨酸特异性去甲基化酶1(LSD1)表达增高,并且LSD1与其发生、发展、增殖、侵袭和转移密切相关。LSD1是一种去甲基酶,其功能依赖黄素腺嘌呤二核苷,能特异性催化组蛋白赖氨酸的去甲基化反应,通过使赖氨酸H3第4位和第9位发生去一甲基、二甲基反应(H3K4me、H3K4me2、H3K9me、H3K9me2),进而调控靶基因的表达。靶向抑制LSD1已被证实能够发挥显著的抗肿瘤效应,但由于肿瘤涉及多个中心和因素,后期的研究发现单一抑制LSD1并不能完全有效杀死肿瘤细胞,并且LSD1催化底物的特异性很大程度上依赖于与其结合的协同因子并形成复合体。基于LSD1的双靶点抑制剂在抑制肿瘤方面呈现出更加显著的效果,所以寻找LSD1结合的协同因子可能会为多靶点抑制剂的研究提供基础。

The expression of histone lysine-specific demethylase 1(LSD1)in colorectal cancer cells is increased,and LSD1 is closely related to its occurrence,development,proliferation,invasion and metastasis.LSD1 is a demethylase whose function depends on flavin adenine dinucleoside.It can specifically catalyze the demethylation reaction of histone lysine,and regulate the expression of target genes by reaction of demethyl and dimethyl(H3K4me,H3K4me2,H3K9me,and H3K9me2)at the 4th and 9th positions of lysine H3.Targeted inhibition of LSD1 has been proved to be able to exert significant anti-tumor effect,but since the tumors involve multiple centers and factors,later studies have found that single inhibition of LSD1 cannot completely and effectively kill tumor cells.Moreover,the specificity of the LSD1 catalytic substrate depends to a large extent on the synergistic factors that bind to it and form complexes.The double-target inhibitors based on LSD1 shows more remarkable effect in tumor inhibition.Therefore,finding the combined synergistic factors of LSD1 may provide the basis for the research of multi-target inhibitors.