LSD1在恶性肿瘤中的研究进展

doi:10.11904/j.issn.1002-3070.2014.06.019

摘要/Abstract

摘要：

赖氨酸特异性组蛋白去甲基化酶(LSD1)是一个黄素腺嘌呤二核苷酸(FAD)依赖性单胺氧化酶,它能够特异性脱去单甲基化和二甲基化 H3K4 和 H3K9 位点上的甲基基团,从而调节基因的转录活性。LSD1对哺乳动物的发育至关重要,并参与许多生物学过程,包括细胞类型的分化、基因活化和基因抑制。目前证实LSD1可促进细胞相变(缺乏LSD1导致部分细胞周期阻滞在G₂/M期)和细胞增殖,提示其过表达可促进肿瘤的发生。LSD1 作为一种去甲基化酶,有可能成为一个新的抗肿瘤治疗靶点。现对LSD1 的结构、作用方式以及其与肿瘤发生的关系等方面进行综述。

关键词: LSD1, 去甲基化, 恶性肿瘤

Abstract:

Lysine specific demethylase 1(LSD1)is a kind of flavin adenine dinucleotid(FAD)dependent amine oxidase and can specifically demethylate H3K4me2/me1 and H3K9me2/mel,thus it can regulate gene transcriptional activity.LSD1 is essential for mammalian development and is involved in many biological processes,including cell differentiation,gene activation,and gene repression.Nowadays,it is demonstrated that LSD1 might promote cell phase transition(deficiency in LSD1 leads to partial cell cycle arrest in G₂/M)and cell proliferation,suggesting that the over-expression of LSD1 might promote tumorigenesis.LSD1,as a demethylase,may be a new target for anti-cancer therapy.Hereby,we review on the structure,action mode of LSD1 and its relationship with oncogenesis.

Key words: LSD1, Demethylation, Malignant tumors

中图分类号:

R730.1

荆璟综述, 陈公琰审校. LSD1在恶性肿瘤中的研究进展[J]. 实用肿瘤学杂志, 2014, 28(6): 569-572.

JING Jing,CHEN Gongyan. The research progress of LSD1 in malignant tumors[J]. PRACTICAL ONCOLOGY JOURNAL, 2014, 28(6): 569-572.

参考文献

1 Olins DE,Olins AL.Chromatin history:our view from the bridge[J].Nat Rev Mol Cell Biol,2003,4(10):809-814.
2 Shi Y,Lan F,Matson C,et al.Histone demethylation mediated by the nuclear amine oxidase homolog LSD1[J].Cell,2004,119(7):941-953.
3 Wang J,Scully K,Zhu X,et al.Opposing LSD1 complexes function in developmental gene activation and repression programmes[J].Nature,2007,446(7138):882-887.
4 Scoumanne A,Chen X.The lysine-specific demethylase 1 is required for cell proliferation in both p53-dependent and-independent manners[J].Biol Chem,2007,282(21):15471-15475.
5 Culhane JC,Cole PA.LSD1 and the chemistry of histone demethylation[J].Curr Opin Chem Biol,2007,11(5):561-568.
6 Aravind L,Iyer LM.The SWIRM domain:a conserved module found in chromosomal proteins points to novel chromatin-modifying activities[J].Genome Biol,2002,3(8):391-397.
7 Yang M,Gocke CB,Luo X,et al.Structural basis for CoREST-dependent demethylase of nucleosomes by the human LSD1 histone demethylase[J].Mol Cell,2006,23(3):377-387.
8 Stavropoulos P,Blobel G,Hoelz A.Crystal structure and mechanism of human lysine-specific demethylase-1[J].Nat Struct Mol Biol,2006,13(7):626-632.
9 Binda C,Mattevi A,Edmondson DE.Structure-function relationship in flavoenzyme-dependent amine oxidations:a comparion of polyamine oxidase an monoamine oxidase[J].J Biol Chem,2002,277(6):23973-23976.
10 Binda C,Newton-Vinson P,Hubalek F,et al.Structure of human monoamine oxidase B,a drug target for the treament of neurological disorders[J].Nat Struct Biol,2002,9(1):22-26.
11 Lee MG,Wynder C,Cooch N,et al.An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation[J].Nature,2005,437(7057):432-435.
12 Anand R,Marmorstein R.Structure and mechanism of lysine-specific demethylase enzymes[J].J Biol Chem,2007,282(49):35425-35429.
13 Huang J,Sengupta R,Espejo AB,et al.p53 is regulated by the lysine demethylase LSD1[J].Nature,2007,449(7158):105-108.
14 Wang J,Hevi S,Kurash JK,et al.The lysine demethylase LSD1(KDM1)is required for maintenance of global DNA methylation[J].Nat Genet,2009,41(1):125-129.
15 Chen T,Li E.Establishment and maintenance of DNA methylation patterns in mammals[J].Curr Top Microbiol Immunol,2006,301(5):179-201.
16 Lan W,Zhang D,Jiang J.The roles of LSD1-mediated epigenetic modifications in maintaining the pluripotency of bladder cancer stem cells[J].Med Hypotheses,2013,81(5):823-825.
17 Siegel R,Naishadham D,Jemal A.Cancer statistics,2012[J].CA Cancer J Clin,2012,62(1):10-29.
18 Kashyap V,Ahmad S,Nilsson EM,et al.The lysine specific demethylase-1(LSD1/KDM1A)regulates VEGF-A expression in prostate cancer[J].Mol Oncol,2013.7(3):555-566.
19 Banerjee S,Kaye SB.New strategies in the treatment of ovarian cancer:current clinical perspectives and future potential[J].Clin Cancer Res,2013,19(5):961-968.
20 Konovalov S,Garcia-Bassets I.Analysis of the levels of lysine-specific demethylase 1(LSD1)mRNA in human ovarian tumors and the effects of chemical LSD1 inhibitors in ovarian cancer cell lines[J].J Ovarian Res,2013,6(1):75-90.
21 Schütte K,Bornschein J,Malfertheiner P.Hepatocellular carcinoma-epidemiological trends and risk factors[J].Dig Dis,2009,27(2):80-92.
22 Zhao ZK,Dong P,Gu J,et al.Overexpression of LSD1 in hepatocellular carcinoma:a latent target for the diagnosis and therapy of hepatoma[J].Tumour Biol,2013,34(1):173-180.
23 Piperi C,Vlastos F,Farmaki E,et al.Epigenetic effects of lung cancer predisposing factors impact on clinical diagnosis and prognosis[J].J Cell Mol Med,2008,12(5):1495-1501.
24 Seligson DB,Horvath S,McBrian MA,et al.Global levels of histone modifications predict prognosis in different cancers[J].Am J Pathol,2009,174(5):1619-1628.
25 Lv T,Yuan D,Miao X,et al.Over-expression of LSD1 promotes proliferation,migration and invasion in non-small lung cancer[J].PLoS One,2012,7(4):e35065.
26 田振囡,胡杨.青年乳腺癌病理特点-附60例病例分析[J].实用肿瘤学杂志,2007,21(4):338-341.
27 Lim S,Janzer A,Becker A,et al.Lysine-specific demethylase 1(LSD1)is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology[J].Carcinogenesis,2010,31(3):512-520.
28 Serce N,Gnatzy A,Steiner S,et al.Elevated expression of LSD1(Lysine-specific demethylase)during tumour progression from pre-invasive to invasive ductal carcinoma of the breast[J].BMC Clin Pathol,2012,12(6):13-17.
29 于妍妍,王斌,陈东风.LSD1及其在肿瘤发生中的调节作用[J].医学综述,2012,18(17):2787-2790.
30 Xu G,Xiao Y,Hu J,et al.The combined effect of retinoic acid and LSD1 siRNA inhibition on cell death in the human neuroblastoma cell line SH-SY5Y[J].Cell Physiol Biochem,2013,31(6):854-862.
31 Singh MM,Manton CA,Bhat KP,et al.Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors[J].Neuro Oncol,2011,13(8):894-903.

[1]	李吉, 陈杨, 张茂镕, 杨昭, 唐娴, 文洪梅. 中国常见消化系统恶性肿瘤伤残调整寿命年归因于人口老龄化的比例分析和趋势预测[J]. 实用肿瘤学杂志, 2025, 39(5): 372-380.
[2]	周素霞, 许志华, 郭淑玲, 范宁, 徐莉立. 2014—2021年青海省肿瘤登记地区恶性肿瘤发病与死亡流行趋势分析[J]. 实用肿瘤学杂志, 2025, 39(5): 381-387.
[3]	刘洋, 王颖, 马祥, 宋家宝, 刘大民, 陈丽莉. 2021年辽宁省营口市城市居民恶性肿瘤发病与死亡分析[J]. 实用肿瘤学杂志, 2025, 39(5): 400-404.
[4]	代晓泽, 马玉霞, 李雨婷, 齐笑晴, 祝天岑, 穆慧娟, 刘辉. 2014—2020年辽宁省阜新市城市居民恶性肿瘤发病与死亡流行趋势分析[J]. 实用肿瘤学杂志, 2025, 39(4): 278-283.
[5]	祝天岑, 礼彦侠, 任方晗, 代晓泽, 刘洋, 穆慧娟. 2021年辽宁省肿瘤登记地区恶性肿瘤流行情况分析[J]. 实用肿瘤学杂志, 2025, 39(4): 294-300.
[6]	李吉, 张茂镕, 杨昭, 文洪梅, 伍福仙, 李云涛. 2020年云南省昆明市肿瘤登记地区恶性肿瘤发病和死亡特征及2016—2020年趋势分析[J]. 实用肿瘤学杂志, 2025, 39(3): 169-176.
[7]	文小焱, 陈俐. 2010年和2020年四川省30岁及以上人群恶性肿瘤疾病负担比较分析[J]. 实用肿瘤学杂志, 2025, 39(1): 1-6.
[8]	陈茂森, 陈杨, 石青萍, 邵英, 唐娴, 任思颖, 文洪梅. 2020年云南省恶性肿瘤发病和死亡分析[J]. 实用肿瘤学杂志, 2024, 38(5): 283-288.
[9]	苏锋, 梁磊, 邓英, 张同蕾, 王艳平. 2016—2020年陕西省安康市恶性肿瘤流行特征和变化趋势分析[J]. 实用肿瘤学杂志, 2024, 38(5): 300-305.
[10]	何佳颖, 朱津丽, 贾凯旋, 杨佩颖. IFN-γ在肿瘤免疫检查点抑制剂治疗中的研究进展[J]. 实用肿瘤学杂志, 2024, 38(5): 330-335.
[11]	刘丽莉, 张雪云, 张雷. 2020—2022年第一师阿拉尔市恶性肿瘤发病分析[J]. 实用肿瘤学杂志, 2024, 38(4): 246-253.
[12]	钟女娟, 马晶昱, 许志达. 2019年福建省福清市恶性肿瘤发病与死亡情况及2015—2019年趋势分析[J]. 实用肿瘤学杂志, 2024, 38(1): 1-6.
[13]	程锦, 王玮. 维甲酸诱导蛋白在消化系统恶性肿瘤中的研究进展[J]. 实用肿瘤学杂志, 2023, 37(6): 502-506.
[14]	赵世博, 陈永峰, 黎惠怡, 符爱珍. Agrin参与恶性肿瘤发生发展的研究现状[J]. 实用肿瘤学杂志, 2023, 37(6): 507-512.
[15]	宋述铭, 李改琴, 张黎峰, 许凯, 毛雯靖, 张光辉. 新疆医科大学附属肿瘤医院2010—2020年恶性肿瘤住院患者流行病学分析[J]. 实用肿瘤学杂志, 2023, 37(5): 389-394.