赖氨酸去甲基化酶6与肿瘤

doi:10.3760/cma.j.issn.1673-422X.2019.05.008

摘要/Abstract

摘要： 赖氨酸去甲基化酶6（KDM6）作为表观遗传修饰中重要的修饰酶参与组蛋白H3的去甲基化调控，在胚胎发育、炎症及疾病发生过程中起至关重要的作用。目前研究表明KDM6参与多种肿瘤（胰腺癌、肠癌、胃癌、乳腺癌、膀胱癌等）的发生发展，影响肿瘤的增殖、转移、预后及化疗耐药，因肿瘤背景不同而发挥着不同的作用。

关键词: 肿瘤, 组蛋白去甲基化酶, 赖氨酸去甲基化酶6

Abstract: Lysine demethylase 6 (KDM6) is involved in the demethylation regulation of histone H3 as an important modification enzyme in epigenetic modification, and plays an important role in embryonic development, inflammation and disease development. Current researches indicate that KDM6 is involved in the occurrence and development of various tumors (pancreatic cancer, colon cancer, gastric cancer, breast cancer, bladder cancer, etc.), affects proliferation, metastasis, prognosis and chemotherapy resistance of tumors, and plays different roles due to different tumor backgrounds.

Key words: Neoplasms, Histone demethylase, Lysine specific demethylase 6

李龙龙，胡孔旺. 赖氨酸去甲基化酶6与肿瘤[J]. 国际肿瘤学杂志, 2019, 46(5): 289-294.

Li Longlong, Hu Kongwang. Lysine demethylase 6 and tumors[J]. Journal of International Oncology, 2019, 46(5): 289-294.

参考文献

［1］ Pedersen MT, Helin K. Histone demethylases in development and disease［J］. Trends Cell Biol, 2010, 20(11): 662-671. DOI: 10.1016/j.tcb.2010.08.011. ［2］Martin C, Zhang Y. The diverse functions of histone lysine methylation［J］. Nat Rev Mol Cell Biol, 2005, 6(11): 838-849. DOI: 10.1038/ nrm1761. ［3］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. DOI: 10.1016/j.cell.2004.12.012. ［4］Ismail T, Lee HK, Kim C, et al. KDM1A microenvironment, its oncogenic potential, and therapeutic significance［J］. Epigenetics Chromatin, 2018, 11(1): 33. DOI: 10.1186/s1307201802033. ［5］Walport LJ, Hopkinson RJ, Schofield CJ. Mechanisms of human histone and nucleic acid demethylases［J］. Curr Opin Chem Biol, 2012, 16(56): 525-534. DOI: 10.1016/j.cbpa.2012.09.015. ［6］Markolovic S, Leissing TM, Chowdhury R, et al. Structure function relationships of human JmjC oxygenasesdemethylases versus hydroxylases［J］. Curr Opin Struct Biol, 2016, 41: 62-72. DOI: 10.1016/j.sbi.2016.05.013. ［7］Hong S, Cho YW, Yu LR, et al. Identification of JmjC domaincontaining UTX and JMJD3 as histone H3 lysine 27 demethylases［J］. Proc Natl Acad Sci U S A, 2007, 104(47): 18439-18444. DOI: 10.1073/pnas.0707292104. ［8］ Walport LJ, Hopkinson RJ, Vollmar M, et al. Human UTY (KDM6C) is a malespecific Nmethyl lysyl demethylase［J］. J Biol Chem, 2014, 289(26): 18302-18313. DOI: 10.1074/jbc.M114.555052. ［9］Shpargel KB, Starmer J, Yee D, et al. KDM6 demethylase independent loss of histone H3 lysine 27 trimethylation during early embryonic development［J］. PLoS Genet, 2014, 10(8): e1004507. DOI: 10.1371/journal.pgen.1004507. ［10］ Welstead GG, Creyghton MP, Bilodeau S, et al. Xlinked H3K27me3 demethylase Utx is required for embryonic development in a sexspecific manner［J］. Proc Natl Acad Sci U S A, 2012, 109(32): 13004-13009. DOI: 10.1073/pnas.1210787109. ［11］ Chung N, Bogliotti YS, Ding W, et al. Active H3K27me3 demethylation by KDM6B is required for normal development of bovine preimplantation embryos［J］. Epigenetics, 2017, 12(12): 1048-1056. DOI: 10.1080/15592294.2017.1403693. ［12］ Lee S, Lee JW, Lee SK. UTX, a histone H3lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program［J］. Dev Cell, 2012, 22(1): 25-37. DOI: 10.1016/j.devcel.2011.11.009. ［13］ Burgold T, Voituron N, Caganova M, et al. The H3K27 demethylase JMJD3 is required for maintenance of the embryonic respiratory neuronal network, neonatal breathing, and survival［J］. Cell Rep, 2012, 2(5): 1244-1258. DOI: 10.1016/j.celrep.2012.09.013. ［14］ Fagerberg L, Hallstrm BM, Oksvold P, et al. Analysis of the human tissuespecific expression by genomewide integration of transcriptomics and antibodybased proteomics［J］. Mol Cell Proteomics, 2014, 13(2): 397406. DOI: 10.1074/mcp.M113.035600. ［15］ Banka S, Lederer D, Benoit V, et al. Novel KDM6A (UTX) mutations and a clinical and molecular review of the Xlinked Kabuki syndrome (KS2)［J］. Clin Genet, 2015, 87(3): 252-258. DOI: 10.1111/cge.12363. ［16］ Burgold T, Spreafico F, De Santa F, et al. The histone H3 lysine 27-specific demethylase Jmjd3 is required for neural commitment［J］. PLoS One, 2008, 3(8): e3034. DOI: 10.1371/journal.pone.0003034. ［17］ Ezponda T, DupéréRicher D, Will CM, et al. UTX/KDM6A loss enhances the malignant phenotype of multiple myeloma and sensitizes cells to EZH2 inhibition［J］. Cell Rep, 2017, 21(3): 628640. DOI: 10.1016/j.celrep.2017.09.078. ［18］ Li SH, Lu HI, Huang WT, et al. The prognostic significance of histone demethylase UTX in esophageal squamous cell carcinoma［J］. Int J Mol Sci, 2018, 19(1): e297. DOI: 10.3390/ijms19010297. ［19］ Nickerson ML, Dancik GM, Im KM, et al. Concurrent alterations in TERT, KDM6A, and the BRCA pathway in bladder cancer［J］. Clin Cancer Res, 2014, 20(18): 4935-4948. DOI: 10.1158/1078-0432.CCR-14-0330. ［20］ Agger K, Cloos PA, Rudkjaer L, et al. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence［J］. Genes Dev, 2009, 23(10): 1171-1176. DOI: 10.1101/gad.510809. ［21］ Salminen A, Kaarniranta K, Hiltunen M, et al. Histone demethylase Jumonji D3 (JMJD3/KDM6B) at the nexus of epigenetic regulation of inflammation and the aging process［J］. J Mol Med (Berl), 2014, 92(10): 1035-1043. DOI: 10.1007/s00109-014-1182-x. ［22］ Yan Q, Sun L, Zhu Z, et al. Jmjd3mediated epigenetic regulation of inflammatory cytokine gene expression in serum amyloid A-stimulated macrophages［J］. Cell Signal, 2014, 26(9): 1783-1791. DOI: 10.1016/j.cellsig.2014.03.025. ［23］ Dutta A, Le Magnen C, Mitrofanova A, et al. Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation［J］. Science, 2016, 352(6293): 1576-1580. DOI: 10.1126/science.aad9512. ［24］ Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types［J］. Nature, 2013, 502(7471): 333-339. DOI: 10.1038/nature12634. ［25］ Gao YB, Chen ZL, Li JG, et al. Genetic landscape of esophageal squamous cell carcinoma［J］. Nat Genet, 2014, 46(10): 1097-1102. DOI: 10.1038/ng.3076. ［26］ Du P, Huang P, Huang X, et al. Comprehensive genomic analysis of oesophageal squamous cell carcinoma reveals clinical relevance［J］. Sci Rep, 2017, 7(1): 15324. DOI: 10.1038/s41598-017-14909-5. ［27］ Zhou Z, Zhang HS, Liu Y, et al. Loss of TET1 facilitates DLD1 colon cancer cell migration via H3K27me3mediated downregulation of Ecadherin［J］. J Cell Physiol, 2018, 233(2): 1359-1369. DOI: 10.1002/jcp.26012. ［28］ Tokunaga R, Sakamoto Y, Nakagawa S, et al. The prognostic significance of histone lysine demethylase JMJD3/KDM6B in colorectal cancer［J］. Ann Surg Oncol, 2016, 23(2): 678-685. DOI: 10.1245/s10434-015-4879-3. ［29］ Pereira F, Barbáchano A, Silva J, et al. KDM6B/JMJD3 histone demethylase is induced by vitamin D and modulates its effects in colon cancer cells［J］. Hum Mol Genet, 2011, 20(23): 4655-4665. DOI: 10.1093/hmg/ddr399. ［30］ Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer［J］. Nature, 2015, 518(7540): 495-501. DOI: 10.1038/nature14169. ［31］ Andricovich J, Perkail S, Kai Y, et al. Loss of KDM6A activates superenhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to BET inhibitors［J］. Cancer Cell, 2018, 33(3): 512-526. DOI: 10.1016/j.ccell.2018.02.003. ［32］ Watanabe S, Shimada S, Akiyama Y, et al. Loss of KDM6A characterizes a poor prognostic subtype of human pancreatic cancer and potentiates HDAC inhibitor lethality［J］. Int J Cancer, 2019, 45(1): 192-205. DOI: 10.1002/ijc.32072. ［33］ Yamamoto K, Tateishi K, Kudo Y, et al. Loss of histone demethylase KDM6B enhances aggressiveness of pancreatic cancer through downregulation of C/EBPα［J］. Carcinogenesis, 2014, 35(11): 2404-2414. DOI: 10.1093/carcin/bgu136. ［34］ Koschmieder S, Halmos B, Levantini E, et al. Dysregulation of the C/EBPalpha differentiation pathway in human cancer［J］. J Clin Oncol, 2009, 27(4): 619-628. DOI: 10.1200/JCO.2008.17.9812. ［35］ Lee SW, Park DY, Kim MY, et al. Synergistic triad epistasis of epigenetic H3K27me modifier genes, EZH2, KDM6A, and KDM6B, in gastric cancer susceptibility［J］. Gastric Cancer, 2019, 22(3): 640-644. DOI: 10.1007/s10120-018-0888-9. ［36］ Jiang Q, Song HJ, Liu Y, et al. KDM6A regulates cell proliferation, invasion and apoptosis by transcriptional inhibits p16(ink4a)［J］. Int J Clin Exp Med, 2017, 10(7): 10297-10305. ［37］ Zhang PP, Wang XL, Zhao W, et al. DNA methylationmediated repression of miR941 enhances lysine (K)specific demethylase 6B expression in hepatoma cells［J］. J Biol Chem, 2014, 289(35): 24724-24735. DOI: 10.1074/jbc.M114.567818. ［38］ Wang J, Liu L, Long Q, et al. Decreased expression of JMJD3 predicts poor prognosis of patients with clear cell renal cell carcinoma［J］. Oncol Lett, 2017, 14(2): 1550-1560. DOI: 10.3892/ol.2017.6362. ［39］ Ler LD, Ghosh S, Chai X, et al. Loss of tumor suppressor KDM6A amplifies PRC2regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2［J］. Sci Transl Med, 2017, 9(378): eaai8312. DOI: 10.1126/scitranslmed.aai8312. ［40］ Kaneko S, Li X. X chromosome protects against bladder cancer in females via a KDM6Adependent epigenetic mechanism［J］. Sci Adv, 2018, 4(6): eaar5598. DOI: 10.1126/sciadv.aar5598. ［41］ Fusco N, Geyer FC, De Filippo MR, et al. Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer［J］. Mod Pathol, 2016, 29(11): 1292-1305. DOI: 10.1038/modpathol.2016.134. ［42］ Choi HJ, Park JH, Park M, et al. UTX inhibits EMTinduced breast CSC properties by epigenetic repression of EMT genes in cooperation with LSD1 and HDAC1［J］. EMBO Rep, 2015, 16(10): 1288-1298. DOI: 10.15252/embr.201540244. ［43］ Kim JH, Sharma A, Dhar SS, et al. UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells［J］. Cancer Res, 2014, 74(6): 1705-1717. DOI: 10.1158/0008-5472.CAN-13-1896. ［44］ Xie G, Liu X, Zhang Y, et al. UTX promotes hormonally responsive breast carcinogenesis through feedforward transcription regulation with estrogen receptor［J］. Oncogene, 2017, 36(39): 5497-5511. DOI: 10.1038/onc.2017.157. ［45］ Wang W, Lim KG, Feng M, et al. KDM6B counteracts EZH2mediated suppression of IGFBP5 to confer resistance to PI3K/AKT inhibitor treatment in breast cancer［J］. Mol Cancer Ther, 2018, 17(9): 1973-1983. DOI: 10.1158/1535-7163.MCT-17-0802. ［46］ Ntziachristos P, Tsirigos A, Welstead GG, et al. Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia［J］. Nature, 2014, 514(7523): 513-517. DOI: 10.1038/nature13605. ［47］ Tsuyama N, Asaka R, Dobashi A, et al. EpsteinBarr virusnegative extranodal "true" natural killercell lymphoma harbouring a KDM6A mutation［J］. Hematol Oncol, 2018, 36(1): 328-335. DOI: 10.1002/hon.2459. ［48］ Ohguchi H, Harada T, Sagawa M, et al. KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival［J］. Leukemia, 2017, 31(12): 2661-2669. DOI: 10.1038/leu.2017.141. ［49］ Gozdecka M, Meduri E, Mazan M, et al. UTXmediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs［J］. Nat Genet, 2018, 50(6): 883-894. DOI: 10.1038/s41588-018-0114-z. ［50］ Wu Q, Tian Y, Zhang J, et al. In vivo CRISPR screening unveils histone demethylase UTX as an important epigenetic regulator in lung tumorigenesis［J］. Proc Natl Acad Sci U S A, 2018, 115(17): 39783986. DOI: 10.1073/pnas.1716589115. ［51］ Ma J, Wang N, Zhang Y, et al. KDM6B elicits cell apoptosis by promoting nuclear translocation of FOXO1 in non-small cell lung cancer［J］. Cell Physiol Biochem, 2015, 37(1): 201213. DOI: 10.1159/000430345. ［52］ Moody CA, Laimins LA. Human papillomavirus oncoproteins: pathways to transformation［J］. Nat Rev Cancer, 2010, 10(8): 550-560. DOI: 10.1038/nrc2886. ［53］ Munger K, Jones DL. Human papillomavirus carcinogenesis: an identity crisis in the retinoblastoma tumor suppressor pathway［J］. J Virol, 2015, 89(9): 4708-4711. DOI: 10.1128/JVI.03486-14. ［54］ Soto DR, Barton C, Munger K, et al. KDM6A addiction of cervical carcinoma cell lines is triggered by E7 and mediated by p21CIP1 suppression of replication stress［J］. PLoS Pathog, 2017, 13(10): e1006661. DOI: 10.1371/journal.ppat.1006661. ［55］ Roussel MF, Stripay JL. Epigenetic drivers in pediatric medulloblastoma［J］. Cerebellum, 2018, 17(1): 28-36. DOI: 10.1007/s12311-017-0899-9. ［56］ SherryLynes MM, Sengupta S, Kulkarni S, et al. Regulation of the JMJD3 (KDM6B) histone demethylase in glioblastoma stem cells by STAT3［J］. PLoS One, 2017, 12(4): e0174775. DOI: 10.1371/journal.pone.0174775. ［57］ Yang L, Zha Y, Ding J, et al. Histone demethylase KDM6B has an antitumorigenic function in neuroblastoma by promoting differentiation［J］. Oncogenesis, 2019, 8(1): 3. DOI: 10.1038/s41389-018-0112-0. ［58］ Panaccione A, Zhang Y, Mi Y, et al. Chromosomal abnormalities and molecular landscape of metastasizing mucinous salivary adenocarcinoma［J］. Oral Oncol, 2017, 66: 38-45. DOI: 10.1016/j.oraloncology.2016.12.011. ［59］ Moreira AL, Won HH, McMillan R, et al. Massively parallel sequencing identifies recurrent mutations in TP53 in thymic carcinoma associated with poor prognosis［J］. J Thorac Oncol, 2015, 10(2): 373-380. DOI: 10.1097/JTO.0000000000000397. ［60］ Cregan S, Breslin M, Roche G, et al. KDM6A and KDM6B: altered expression in malignant pleural mesothelioma［J］. Int J Oncol, 2017, 50(3): 1044-1052. DOI: 10.3892/ijo.2017.3870.

[1]	刘娜, 寇介丽, 杨枫, 刘桃桃, 李丹萍, 韩君蕊, 杨立洲. 血清miR-106b-5p、miR-760联合低剂量螺旋CT诊断早期肺癌的临床价值[J]. 国际肿瘤学杂志, 2024, 51(6): 321-325.
[2]	杨蜜, 别俊, 张加勇, 邓佳秀, 唐组阁, 卢俊. 局部晚期可切除食管癌新辅助治疗疗效及预后分析[J]. 国际肿瘤学杂志, 2024, 51(6): 332-337.
[3]	袁健, 黄燕华. Hp-IgG抗体联合血清DKK1、sB7-H3对早期胃癌的诊断价值[J]. 国际肿瘤学杂志, 2024, 51(6): 338-343.
[4]	陈红健, 张素青. 血清miR-24-3p、H2AFX与肝癌患者临床病理特征及术后复发的关系研究[J]. 国际肿瘤学杂志, 2024, 51(6): 344-349.
[5]	郭泽浩, 张俊旺. PFDN及其亚基在肿瘤发生发展中的作用[J]. 国际肿瘤学杂志, 2024, 51(6): 350-353.
[6]	张百红, 岳红云. 新作用机制的抗肿瘤药物进展[J]. 国际肿瘤学杂志, 2024, 51(6): 354-358.
[7]	许凤琳, 吴刚. EBV在鼻咽癌肿瘤免疫微环境和免疫治疗中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 359-363.
[8]	王盈, 刘楠, 郭兵. 抗体药物偶联物在转移性乳腺癌治疗中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 364-369.
[9]	张蕊, 褚衍六. 基于FIT与肠道菌群的结直肠癌风险评估模型的研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 370-375.
[10]	高凡, 王萍, 杜超, 褚衍六. 肠道菌群与结直肠癌非手术治疗的相关研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 376-381.
[11]	王丽, 刘志华, 杨伟洪, 蒋凤莲, 李全泳, 宋浩杰, 鞠文东. ROS1突变肺腺鳞癌合并脑梗死为主要表现的Trousseau综合征1例[J]. 国际肿瘤学杂志, 2024, 51(6): 382-384.
[12]	刘静, 刘芹, 黄梅. 基于SMOTE算法的食管癌放化疗患者肺部感染的预后模型构建[J]. 国际肿瘤学杂志, 2024, 51(5): 267-273.
[13]	杨琳, 路宁, 温华, 张明鑫, 朱琳. 炎症负荷指数与胃癌临床关系研究[J]. 国际肿瘤学杂志, 2024, 51(5): 274-279.
[14]	王俊毅, 洪楷彬, 纪荣佳, 陈大朝. 癌结节对结直肠癌根治性切除术后肝转移的影响[J]. 国际肿瘤学杂志, 2024, 51(5): 280-285.
[15]	张宁宁, 杨哲, 檀丽梅, 李振宁, 王迪, 魏永志. 宫颈细胞DNA倍体分析联合B7-H4和PKCδ对宫颈癌的诊断价值[J]. 国际肿瘤学杂志, 2024, 51(5): 286-291.