组蛋白去乙酰化酶抑制剂在卵巢癌靶向治疗中的作用研究
|
摘要
目的:探讨组蛋白去乙酰化酶(Histone deacetylase,HDAC)基因及其蛋白表达检测在卵巢浆液性癌中的临床病理学意义以及HDACs抑制剂曲古抑菌素A(Trichostatin A,TSA)在卵巢癌分子靶向治疗中的作用。
材料与方法:39例卵巢浆液性囊腺瘤(Serous benign tumors),26例卵巢浆液性交界性囊腺瘤(Serous borderline tumors)和82例卵巢浆液性囊腺癌(Serousadenocarcinoma)共147例卵巢病变的存档蜡块标本选自延边妇幼保健院、延边肿瘤医院和美国约翰.霍普金斯大学医学院病理科。同时,选取两种正常卵巢上皮细胞系IOSE-29和IOSE-329以及三种卵巢癌细胞系ES-2、SKOV-3、OVCAR-8作为TSA体外治疗效应的检测对象。应用免疫荧光技术方法观察HDAC6和HDAC1蛋白在SKOV-3细胞中的定位,并应用免疫组化方法检测HDAC6和HDAC1基因蛋白在卵巢浆液性良性、交界性囊腺瘤和浆液性囊腺癌组织中的表达变化。应用小分子RNA干扰和XTT检测技术等测定广谱HDACs抑制剂TSA对于卵巢癌细胞的体外杀伤作用及其机制。
结果:免疫荧光染色结果表明,HDAC6蛋白定位于SKOV-3卵巢癌细胞浆内,呈颗粒样弥散分布,而HDAC1蛋白则定位于SKOV-3细胞核。免疫组化染色结果也表明HDAC6和HDAC1蛋白分别为胞浆和胞核染色,而RHDAC6蛋白强阳性表达率在卵巢浆液性囊腺瘤中为0(0/39),而在交界性浆液性肿瘤中为34.6%(9/26)、在浆液性囊腺癌中则高达86.6%(71/86);HDAC1蛋白强阳性表达率在卵巢浆液性囊腺瘤,交界性浆液性肿瘤和浆液性囊腺癌中分别为7.7%(3/39)、65.4%(17/26)和80.5%(66/82)。TSA对于ES-2、SKOV-3、OVCAR-8等卵巢癌细胞系具有明显的体外杀伤作用,但正常的卵巢上皮细胞系IOSE-29和IOSE-329则对TSA不敏感。
结论:HDAC6和HDAC1蛋白检测对于卵巢浆液性癌的诊断具有重要的辅助意义,而且有望成为卵巢癌治疗的新靶点。同时,HDACs抑制剂TSA对于卵巢癌具有明显的体外杀伤作用。
Objectives:To investigate the clinico-pathological significance of Histone Deacetylase(HDACs) expression in ovarian serous tumors,and the killing effect of HDACs inhibitor,trichostatin A(TSA),on the molecular target therapy for ovarian serous adenocarcinoma.
Materials and Methods:Total 147 cases of paraffin embedded ovarian lesion blocks,including 39 cases of serous benign tumors,26 cases of serous borderline tumors,and 82 cases of serous adenocarcinoma were selected from Dept.of Pathology,Yanbian Women's Hospital,Yanbian Tumor Hospital,and Johns Hopkins University Medical Institutions.The killing effect of TSA on ovarian cancers was detected by using XTT on the two of normal ovarian epithelial cell lines,IOSE-29 and IOSE-329,and three of ovarian cancer cell lines,ES-2,SKOV-3,and OVCAR-8. The protein expression of HDAC6 and HDAC1 were detected by immunohistochemistry,Western Blot,and immunofluorescence staining.Also, HDAC6 siRNA transfection and XTT detection methods were used for investigating the killing mechanism of TSA on ovarian cancers.
Results:HDAC6 and HDAC1 proteins were located in the plasma and nucleus of SKOV-3 cells by immunofluorescence,respectively.Immunohistochemical staining showed that HDAC6 protein was negative in all 39 cases of serous benign tumors, however,the strongly positive rate of HDAC6 protein were 34.6%(9/26) and 86.6% (71/86) in serous borderline tumors and serous adenocarcinomas,respectively. Similarly,the strongly positive rate of HDAC1 protein was 7.7%(3/39),65.4%(17/26) and 80.5%(66/82) in serous cystadenoma,serous borderline tumor,and serous adenocarcinoma,respectively.Also,all of ES-2,SKOV-3,and OVCAR-8 ovarian cancer cells were very sensitive for TSA treatment than IOSE-29 and IOSE-329 normal ovarian epithelial cells.
Conclusions:The detection of HDAC6 and HDAC1 protein expression could be used as affiliated markers for the early diagnosis of ovarian cancer,and HDAC6 might be the molecular target for the ovarian cancer therapy.HDACs inhibitor,TSA, could effectively kill the ovarian cancer cells.
材料与方法:39例卵巢浆液性囊腺瘤(Serous benign tumors),26例卵巢浆液性交界性囊腺瘤(Serous borderline tumors)和82例卵巢浆液性囊腺癌(Serousadenocarcinoma)共147例卵巢病变的存档蜡块标本选自延边妇幼保健院、延边肿瘤医院和美国约翰.霍普金斯大学医学院病理科。同时,选取两种正常卵巢上皮细胞系IOSE-29和IOSE-329以及三种卵巢癌细胞系ES-2、SKOV-3、OVCAR-8作为TSA体外治疗效应的检测对象。应用免疫荧光技术方法观察HDAC6和HDAC1蛋白在SKOV-3细胞中的定位,并应用免疫组化方法检测HDAC6和HDAC1基因蛋白在卵巢浆液性良性、交界性囊腺瘤和浆液性囊腺癌组织中的表达变化。应用小分子RNA干扰和XTT检测技术等测定广谱HDACs抑制剂TSA对于卵巢癌细胞的体外杀伤作用及其机制。
结果:免疫荧光染色结果表明,HDAC6蛋白定位于SKOV-3卵巢癌细胞浆内,呈颗粒样弥散分布,而HDAC1蛋白则定位于SKOV-3细胞核。免疫组化染色结果也表明HDAC6和HDAC1蛋白分别为胞浆和胞核染色,而RHDAC6蛋白强阳性表达率在卵巢浆液性囊腺瘤中为0(0/39),而在交界性浆液性肿瘤中为34.6%(9/26)、在浆液性囊腺癌中则高达86.6%(71/86);HDAC1蛋白强阳性表达率在卵巢浆液性囊腺瘤,交界性浆液性肿瘤和浆液性囊腺癌中分别为7.7%(3/39)、65.4%(17/26)和80.5%(66/82)。TSA对于ES-2、SKOV-3、OVCAR-8等卵巢癌细胞系具有明显的体外杀伤作用,但正常的卵巢上皮细胞系IOSE-29和IOSE-329则对TSA不敏感。
结论:HDAC6和HDAC1蛋白检测对于卵巢浆液性癌的诊断具有重要的辅助意义,而且有望成为卵巢癌治疗的新靶点。同时,HDACs抑制剂TSA对于卵巢癌具有明显的体外杀伤作用。
Objectives:To investigate the clinico-pathological significance of Histone Deacetylase(HDACs) expression in ovarian serous tumors,and the killing effect of HDACs inhibitor,trichostatin A(TSA),on the molecular target therapy for ovarian serous adenocarcinoma.
Materials and Methods:Total 147 cases of paraffin embedded ovarian lesion blocks,including 39 cases of serous benign tumors,26 cases of serous borderline tumors,and 82 cases of serous adenocarcinoma were selected from Dept.of Pathology,Yanbian Women's Hospital,Yanbian Tumor Hospital,and Johns Hopkins University Medical Institutions.The killing effect of TSA on ovarian cancers was detected by using XTT on the two of normal ovarian epithelial cell lines,IOSE-29 and IOSE-329,and three of ovarian cancer cell lines,ES-2,SKOV-3,and OVCAR-8. The protein expression of HDAC6 and HDAC1 were detected by immunohistochemistry,Western Blot,and immunofluorescence staining.Also, HDAC6 siRNA transfection and XTT detection methods were used for investigating the killing mechanism of TSA on ovarian cancers.
Results:HDAC6 and HDAC1 proteins were located in the plasma and nucleus of SKOV-3 cells by immunofluorescence,respectively.Immunohistochemical staining showed that HDAC6 protein was negative in all 39 cases of serous benign tumors, however,the strongly positive rate of HDAC6 protein were 34.6%(9/26) and 86.6% (71/86) in serous borderline tumors and serous adenocarcinomas,respectively. Similarly,the strongly positive rate of HDAC1 protein was 7.7%(3/39),65.4%(17/26) and 80.5%(66/82) in serous cystadenoma,serous borderline tumor,and serous adenocarcinoma,respectively.Also,all of ES-2,SKOV-3,and OVCAR-8 ovarian cancer cells were very sensitive for TSA treatment than IOSE-29 and IOSE-329 normal ovarian epithelial cells.
Conclusions:The detection of HDAC6 and HDAC1 protein expression could be used as affiliated markers for the early diagnosis of ovarian cancer,and HDAC6 might be the molecular target for the ovarian cancer therapy.HDACs inhibitor,TSA, could effectively kill the ovarian cancer cells.
引文
[1]周蔚,李留霞.卵巢癌的靶向基因治疗研究进展.国外医学妇产科学分册,2006,33(5):424-427.
[2]谢爱华,廖晨钟,李伯玉,等.以组蛋白去乙酰化酶为靶标的抗癌药物研发进展.中国新药杂志,2005,14(1):10-14.
[3]林贞花.子宫及卵巢肿瘤病理基础研究中的几点问题.中华病理学杂志,2007,36(8):508-510.
[4]Micha JP,Goldstein BH,Rettenmaier MA,et al.Clinical utility of CA-125 for maintenance therapy in the treatment of advanced stage ovarian carcinoma,lnt J Gynecol Cancer,2009,19(2):239-241.
[5]Kumar S,Bryant CS,Chamala S,et al.Ritonavir blocks AKT signaling,activates apoptosis and inhibits migration and invasion in ovarian cancer cells.Mol Cancer,2009,8(1):26.
[6]Lee YS,Lim KH,Guo X,et al.The cytoplasmic deacetylase HDAC6 is required for efficient oncogenic tumorigenesis.Clin Cancer Res,2008,68(18):7561-7569.
[7]Hildmann C,Wegener D,Riester D,et al.Substrate and inhibitor specificity of class 1 and class 2 histone deacetylases.JBiotechnol,2006,124(1):258-270.
[8]Li H,Wu X.Histone deacetylase inhibitor,Trichostatin A,activates p21WAF1/CIP1 expression through downregulation of c-myc and release of the repression of c-myc from the promoter in human cervical cancer cells.Biochem Biophys Res Commun,2004,324(2):860-867.
[9]Bi G,Jiang G.The molecular mechanism of HDAC inhibitors in anticancer effects.Cell Mol Immunol,2006,3(4):285-290.
[10]Schafer S,Saunders L,Eliseeva E,et al.Phenylalanine-containing hydroxamic acids as selective inhibitors of class lib histone deacetylases(HDACs).Bioorg Med Chem,2008,16(4):2011-2033.
[11]Fischle W,Kiermer V,Dequiedt F,et al.The emerging role of class Ⅱ histone deacetylases.Biochem Cell Biol,2001,79(3):337-348.
[12]Crazzolara R,Johrer K,Johnstone RW,et al.Histone deacetylase inhibitom potently repress CXCR4 chemokine receptor expression and function in acute lymphoblastic leukaemia.Br J Haematol,2002,119(4):965-969.
[13]Choi JH,Kwon HJ,Yoon BI,et al.Expression profile of histone deacetylase 1 in gastric cancer tissues.Jpn J Cancer Res,2001,92(12):1300-1304.
[14]殷红.组蛋白去乙酰化异常与恶性肿瘤.国外医学生理病理科学与临床分册,2003,23(3):238-241.
[15]Hildmann C,Wegener D,Riester D,et al.Substrate and inhibitor specificity of class 1 and class 2 histone deacetylases.JBiotechnol,2006,124(1):258-270.
[16]Schafer S,Saunders L,Eliseeva E,et al.Phenylalanine-containing hydroxamic acids as selective inhibitors of class IIb histone deacetylases(HDACs).Bioorg Med Chem,2008,16(4):2011-2033.
[17]Li H,Wu X.Histone deacetylase inhibitor,Trichostatin A,activates p21WAF1/CIP1 expression through downregulation of c-myc and release of the repression of c-myc from the promoter in human cervical cancer cells.Biochem Biophys Res Commun,2004,324(2):860-867.
[18]Bi G,Jiang G.The molecular mechanism of HDAC inhibitors in anticancer effects.Cell Mol Immunol,2006,3(4):285-290.
[19]Suzuki T,Kouketsu A,Itoh Y,et al.Highly potent and selective histone deacetylase 6 inhibitors designed based on a small-molecular substrate.J Med Chem,2006,49(16):4809-4812.
[20]Iwata A,Riley BE,Johnston JA,et al.HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin.J Biol Chem,2005,280(48):40282-40292.
[21]Bali P,Pranpat M,Bradner J,et al.Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90:a novel basis for antileukemia activity of histone deacetylase inhibitors,d Biol Chem,2005,280(29):26729-26734.
[22]Iwata A,Riley BE,Johnston JA,et al.HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin.J Biol Chem,2005,280(48):40282-40292.
[23]Heltweg B,Deguiedt F,Marshall BL,et al.Subtype selective substrates for histone deacetylases.J Med Chem,2004,47(21):5235-5243.
[24]Matthias P,Youshida M,Khochbin S.HDAC6 a new cellular stress surveillance factor.Cell Cycle,2008,7(1):7-10.
[25]Gao YS,Hubbert CC,Lu J,et al.Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis.Mol Cell Biol,2007,7(24):8637-8647.
[26]Zhang Z,Yamashita H.Toyama T,et al.HDAC6 expression is correlated with better survival in breast cancer.Clin Cancer Res,2004,10(20):6962-6968.
[27]Wu P,Meng L,Wang H,et al.Role of hTERT in apoptosis of cervical cancer induced by histone deacetylase inhibitor.Biochem Biophys Res Commun,2005,335(1):36-44.
[28]Khabele D,Son DS,Parl AK,et al.Rice VM.Drug-induced inactivation or gene silencing of class I histone deacetylases suppresses ovarian cancer cell growth implications for therapy.Cancer Biol Ther,2007,6(5):759-801.
[29]Bazzaro M,Lin Z,Santillan A,et al.Ubiquitin Proteasome System Stress Underlies Synergistic Killing of Ovarian Cancer Cells by Bortezomib and a Novel HDAC6 Inhibitor.Clin Cancer Res,2008,14(22):7340-7347.
[30]韦进钟,林庆华,谢明权,等.组蛋白脱乙酰酶抑制剂apicidin及其类似物的抗原虫与抗肿瘤作用研究进展.中国新药杂志,2005,14(2):146-150.
[31]Han ES,Lin P,Wakabayashi M.Current status on biologic therapies in the treatment of epithelial ovarian cancer.Curr Treat Options Oncol,2009,Epub ahead of print.
[32]Bijman MN,van Berkel MP,Kok M,et al.Inhibition of functional HER family members increases the sensitivity to docetaxel in human ovarian cancer cell lines.Anticancer Drugs,2009,Epub ahead of print.
[33]Yap OW,Bhat G,Liu L,et al.Epigenetic modifications of the Estrogen receptor beta in epithelial ovarian cancer cells.A nticancer Res,2009,29(1):139-144.
[34]Crazzolara R,Johrer K,Johnstone RW,et al.Histone deacetylase inhibitom potently repress CXCR4 chemokine receptor expression and function in acute lymphoblastic leukaemia.Br J Haematol,2002,119(4):965-969.
[35]Shen C,Buck A K,Liu X,et al.Gene silencing by adenovirusdelivered siRNA.FEBS Lelett,2003,539(27):111-114.
[36]Gramil M,Thelen P,Hemmerlein B,et al.Bax inhibitior-1 is overexpressed in prostate cancer and its specific downregulation by RNA interference leads to cell death in human prostate carcinoma cells.Am JPathol,2003,163(2):543-552.
[37]Villa R,Morey L,Raker VA,et al.The methyl-CpG binding protein MBD1 is required for PML-RARalpha function.Proc NatlAcadSci USA,2006,103(5):1400-1405.
[38]Kramer OH,Muller S,Buchwald M,et al.Mechanism for ubiquitylation of the leukemia fusion proteins AML1-ETO and PML-RARalpha.FASEB J,2008,22(5):1369-1379.
[39]Sonnemann J,Kumar KS,Heesch S,et al.Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation,etoposide,and TRAIL in medulloblastoma cells.Int J Oncol,2006,28(3):755-766.
[40]曲巍,王立明,朱有华.组蛋白去乙酰酶抑制剂联合抗癌药物抑制膀胱癌的实验研究.实用医药杂志,2008,25(5):592-594.
[41]李光明,卢启明.HDAC6表达载体转染对胃癌细胞株SGC-7901生物学行为的影响.第四军医大学学报,2008,29(17):1614-1617.
[42]Saji S,Kawakami M,Hayashi S,et al.Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer.Oncogene,2005,24(28):4531-4539.
[43]黄宏,张珍祥,徐永健,等.HDAC1在肺腺癌细胞株A549中的表达及TSA对细胞增殖、凋亡的影响.中国癌症杂志,2003,22(9):922-926.
[44]Boyault C,Sadoul K,Pabion M,et al.HDAC6,at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination.Oncogene,2007,26(37):5468-5476.
[45]Bordoli L,Netsch M,Luthi U,et al.Plant orthologs of p300 / CBP:conservation of a core domain in metazoan p300 / CBP acetyhransferaserelated proteins.Nucleic Acids Res,2001,29:589-597.
[46]Chen G.Wang BB,Li FJ,et al.Enhancive effect of histone deacetylase inhibitor trichostatin A on transfection efficiency of adenovirus in ovarian carcinoma cell line A2780.Ai Zheng,2005,24(10):1196-1200.
[47]陈刚,王蓓蓓,李辅军,等.HDAC抑制剂TSA增强卵巢癌细胞株A2780对腺病毒基因转染效率的体外研究.癌症,2005,24(10):1196-1200.
[48]Kim D H,Rossi J J.Strategies for silencing human disease using RNA interference.Nat Rev Genet,2007,8(3):173-184.
[49]Jiang L,Chen R,Li J,et al.Inhibition of cyclin E expression and cell proliferation by small interfering RNA in breast cancer MCF-7 cell line.Chinese Journal of Cell BiologY,2006,28:188.
[50]Guan H,Xue X,Wang X,et al.siRNA against survivin coupling with epirubicin enhances to induce breast cancer cell MCF-7 to apoptosis.J Sichuan Univ(Med Sci Edi),2006,37(2):221.
[51]孙红,耿利民,杜萍,黄辰.RNA干扰Survivin基因对Hela细胞凋亡及抗肿瘤药物敏感性的影响.第四军医大学学报,2008,29(20):1843-1846.
[52]王毓,刘培淑,毛洪鸾,等.RNA干扰靶向沉默FLIP基因对卵巢癌细胞A2780生物学特性的影响及生长抑制作用.山东大学学报(医学版),2008,46(2):154-158.
[53]张孟贤,韩娜,于世英.RNA干扰沉默HDAC1基因对大肠癌细胞增殖和凋亡的影响.世界华人消化杂志,2008,16(11):1173-1178.
[1]薛京伦.2006.表观遗传学-原理、技术与实践.上海:上海科学技术出版社.
[2]Fraga MF,Ballestar E,Paz MF,et al.2005.Epigenetic differences arise during the lifetime of monozygotic twins.Proceedings of the National Academy of Science of the United States of America,102(30):10604-10609.
[3]Van Speybreeck L.From to epigenesis to epig enetics:the case ofC.H.Waddington.Ann NYAcad Sci,2002,981:7-49.
[4]Bird A.Perceptions of epigenetics.Nature,2007,447(7143):396-398.
[5]Jones PA,Baylin SB.T he fundamental role of epigenetic events in cancer.Nat Rev Genet,2002,3(6):415-428.
[6]Jaenisch R,Bird A.2003.Epigenetic regulation of gene expression:how the genome integrates intrinsic and environmental signals.Nature Reviews Genetics,33(4):245-254.
[7]Feinbeg A P,Tycko B.The history of caltlcer epigenetics.Nat Rev Cancer,2004,4:143-153.
[8]Robertson KD.DNA methylation and human disease.Nat Rev Genel,2005,6:597-610.
[9]Rakyan VK,Hildmann T,Novik KL,et al.DNAmethylation profiling of the human major histocompatibility complex:a pilot study for the human epigenome project.PLoS Biod,2004,2:e405.
[10]张丽丽,吴建新.2006.DNA甲基化-肿瘤产生的一种表观遗传学机制.遗传,28(7):880-885.
[11]Jones PA,Martienssen R.A blueprint for a Human Epigenome Workshop.Cancer Res,2005,65:11241-11246.
[12]Macaluso M,Paggi MG,Giardano A.Genetic and epigenetic alterations as hallmarks of the intrcate road to cancer.Oncogene.2003,22:6472-6478.
[13]Laird PW.The power and the promise of DNA methylation markers.Nat Rev Cancer,2003,3:253-266.
[14]Scanlan MJ,Simpson AJ,Old LJ.The cancer/testis genes:review,standardi zation, and conmmnentary . Cancer Immun, 2004,4:1.
[15] Socko D. How an imprint can lead to cancer, CMA J, 2005,172: 1286.
[16] Callou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic. Diabetes, 2005, 54:1899-1906.
[17] Davis CD, Hord NG. Nutritional "omics" technologies for Elucidating the role(s) of bioactive food components in colon cancer prevention. J Nutr, 2005, 135: 2694-2697.
[18] Pham AD, Sauer F. Ubiquitin-activating/conjugating activity of TAFn250, a mediator of activation of gene expression in Drosophila. Science, 2000, 289: 2357-2360.
[19] Sassone-Corai P, Mizzen CA, Cheung P, et al. Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3. Science, 1999, 285: 886-891.
[20] Nakayama J, Rice JC, Strahl BD, et al. Role of histone H3 lysine 9 methylation in epigenetic control of heterechrematin assembly. Science, 2001,292: 110-113.
[21] Lattal KM, Barrett RM, Wood MA. Systemic or intrahippocampal delivery of histone deacetylase inhibitors facilitates fear extinction. Behav Neurosci, 2007, 121(5): 1125-1131.
[22] Zhao TC, Cheng G, Zhang LX, et al. Inhibition of histone deacetylases triggers pharmacologic preconditioning effects against myocardial ischemic injury. Cardiovasc Res, 2007, 76(3): 473-481.
[23] Rao J, Bhattacharya D, Banerjee B, et al. Trichostatin-A induces differential changes in histone protein dynamics and expression in HeLa cells. Biochem Biophys Res Commun, 2007, 363(2): 263-268.
[24] Mai A, Perrone A, Nebbioso A, et al. Novel uracil-based 2-aminoanilide and 2-aminoanilide-like derivatives: histone deacetylase inhibition and in-cell activities. BioorgMedChem Lett, 2008, 18(8): 2530-2535.
[25] Mizzen CA, Allis CD. Linking histone acetylation to transcriptional regulation. Cell Mol Life Sci, 1998, 54: 6-20.
[26]Mazzarelli P,Pucci S,Bonanno E,et aI.Camitine palmitoyltransferase Ⅰ in man carcinomas:a novel role in histone deacetylation? Cancer Biol Ther,2007,6(10):1606-1613.
[27]Condorelli F,Gnemmi I,Vallario A,et al.Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells.Br J Pharraacol,2008,153(4):657-668.
[28]Gopal YN,Van Dyke MW.Depletion of histone deacetylase protein:a common consequence of inflammatory cytokine signaling? Cell Cycle,2006,5(23):2738-2743.
[29]Lipinski KS,Fax P.W ilker B,et al.Differences in the interactions of oncogenic adenovirus 12 early region 1A and nononcogenic adenovirus 2early region 1 A with the cellular coactivators p300 and CBP.Virology,1999,255:94-105.
[30]Versteege I,Sevenet N,Lange J,et al.Truncating mutations of hSNFS/INI1 in aggressive paediatric cancer.Nature,1998,394:203-206.[31]Giordano A.Avantaggiati ML.p300 and CBP:partners for life and death.J Cell Physiol,1999,181:218-230.
[32]He LZ,Guidez F,Tribioli C,et al.Distinct interactions of PML-RAR a and PLZF-RAR a with co-repressora determine differential resents to RA in APL.Nat Genet.1998,18:126-135.
[33]Lutterbach B,Westendorf JJ,Linggi B,et al.ETO,a target of t(8;21)in acute leukemia,jnteracts with the N-CoR and rosin3 corepressors.Mol Cell Biol,1998,18:7176-7184.
[34]Bordoli L,Netsch M,Luthi U,et al.Plant orthologs of p300/CBP:conservation of a core domain in metazoan p300/CBP acetyhransferaserelated proteins.Nucleic Acids Res,2001,29:589-597.
[35]刘飞,靳飞,翟晓巧,等.组蛋白甲基化和去甲基化研究进展.中国衣业通报,2007,23(2):56-59.
[36]PetersonC L,LanielM A.Histones and hlstone modifications.Ctnr.Biol,2004,14:R546-551.
[37]Malguoron R,Trojor P,Reinberg D.The key to development:interpreting the histone code? Cmr. Opin. Genet. Dev, 2005,15:163-176.
[38] Bannister A J, Schneider R, Kouzarides T. Histone methylation: dynamic or static?Cell, 2002,109: 801-806.
[39] Petr L. A plant dialect of the histone language. Trend in Plant Science, 2004, 9:84-90.
[40] Tschierseh B, Hofmann A, Krauss V, et al. The protein encoded by the Drosophila position-effect variegation suppressor gene Su(var)3-9 combines domains of antagonistic regulators of homeotic gene complexes. EMBO J, 1994,13: 3822-3831.
[41] ReaS, EisenhaberF, BrianD, et al. Regulation of chromatin structlure by sitespecific histone H3 methyltransferases. Nature, 2000,406: 593-599.
[42] Bannister A J, Zegerman P, Partridge J F, et al. Selective recognition Of methyhted lysine 9 on histone H3 by the HP1 chromo domain. Nature, 2001, 410: 120-124.
[43] Fischle W, Wang Y, Jacobs S A, et al. Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomaim. Genes Dov, 2003,17:1870-1881.
[44] Nakayama J, Rice J C, StrahlB D, et al. Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science, 2001, 292:110-113
[45] Peters A H F M, Kubicek S, Mechtlor K, et al. Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol.Cell, 2003, 12: 1577-1589.
[46] Rice J C, Briggs S D, UeberheideB, et al. Histonemethyltramfemses direct diferent degrees of methylation to define distinct chromatin domains. Mol. Cell, 2003,12:1591-1598.
[47] Eissenberg J C, Elgin SC. The HP1 protein family: getting a grip on Chromatin. Curt. Opin. Genet. Dev, 2000, 10: 204-210.
[48] Tachibana M, Ueda J, Fukuda M, et al. Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev, 2005,19: 815-826.
[49] Tachibana M, Sugimoto K, Nozaki M, et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev, 2002,16:1779-1791.
[50] Ayyanathan K, Lechner M S, Bell P, et al. Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing:a mammalian cell culture model of gene variegation. Genes Dev, 2003, 17: 1855-1869.
[51] Elgin S C R, Grewal, S I S. Heterochromatin: silence is golden. Curt. Biol, 2003, 13: R895-898.
[52] Partridge J F, Borgstrom B, Allshire R C. Distinct protein interaction domains and protein spreading in a complex centromere. Genes Dev, 2000, 14: 783-791.
[53] Partridge J F, Scott K S, Bannister A J, et al. Cis-acting DNA from fission yeast centromeres mediates histone H3 methylation and recruitment of silencing factors and cohesin to an ectopic site. Curt. Biol, 2002, 12: R1652-1660.
[54] Verdel A, Jia S, Gerber S, et al. RNAi-mediated targeting of heterochromatin by the RITS complex. Science, 2004, 303: 672-676.
[55] Sugiyama T, Cam H, Verdel, et al. RNA-dependent RNA polymerase is an essential component of a self-enforcing loop coupling heterochromatin assembly to siRNA production. Proc. Natl Acad. Sci, 2005,102: 152-157.
[56] Andreas H, Demidov D, Gernand D, et al. Methylation of histone H3 in euchromatin of plant chromosomes depends on basic nuclear DNAcontent. The Plant Journal, 2003, 33: 967-973.
[57] Briggs S, BrykM, StrahlM D, et al. Histone H3 lysine 4 methylation Is mediated by Setl and required for cell growth and rDNA silencing in Saccharomyees cerevisiae. Genes Dev, 2001,15: 3286-3295.
[58] Santos-Rosa H, Schneider R, Bannister A J. et al. Active genes are trimethylated at K4 ofhistone H3. Nature, 2002, 419: 407-411.
[59] Ng H H, Robert F, Young R A, et al. Targeted recruitment of Setl histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity. Mol Cell, 2003,11: 709-719.
[60] Pray-Grant M G, Daniel J A, Schieltz D, et al. Chdl chromodomain links histone H3 methylation with SAGA-and SLIK-dependent aeetylation. Naturo, 2005, 433: 434-438.
[61] Wysocka J, Swigut T, Mitne T, et al. WDR5 associates with histone H3 methylated at K4 and is essential for H3-K4 methylation and vertebrate development. Cell, 2005,121: 859-872.
[62] Dou Y, Mitne T A, Tacket A J, et al. Physical association and coordinate function of the H3-K4 methyltransferase MLLland the H4 K16 acetyltransferase MOF.Cell, 2005,121:873-885.
[63] Xiao T, Hall H, Kizer K O, et al. Phosphorylation of RNA polymerase II CTD regulates H3 methylation in yeast. Genes Dev, 2003,17: 654663.
[64] Krogan N J, Kim M, Tong A, et al. Methylation of histone H3 by Set2 in Saccharomyces cerevisiae is linked to transcriptional elongation by RNA polymerase II. Mol. Cell. Biol. 2003,23: 4207-4218.
[65] Li B, Howe L, Anderson S, et al. The Set2 histone methyltransferase functions through the phosphorylated carboxyl-terminal domain of RNA polymeras II. J. Biol. Chem, 2003, 278: 8897-8903.
[66] Wysocka J, Milne T A, Allis C D. Taking LSDI to a New High. Cell, 2005, 122: 654-658.
[67] Paik W, Kim S. Enzymatic demethylation of calf thymus histones. Biochem. Biophys. Res. Commun, 1973, 51: 781-788.
[68] Shi Y, Lan F, Matson C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSDI. Cell, 2004,119: 941-953.
[69] Hakimi M, Bochar D A, Chenoweth J, et al.A Cole-BRAF35 comple containing histone deacetylase mediates repression of neuronal-specific genes. Proc. Natl Acad. Sci, 2002, 99: 7420-7425.
[70] Shi Y J, Sawada J I, Sui G, et al. Coordinated histene modifications mediated by a CtBP co-repressor complex. Nature, 2003 422:735-738.
[71] Hakimi M, Dong Y, Lane W S, et al. A candidate X-linked mental Retardation gene is a component of a new family of histone deacetylase-containing complexes. J. Biol. Chem, 2003,278: 7234-7239.
[72] Lee M J, WynderC, CochN, et al. An essential role for CoREST in Nucleosomal histone 3 lysine 4 demethylation. Nature, 2005,437:432-435.
[73] Metzger E, Wissmann M, Yin N, et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature, 2005, 437: 436-439.
[74] Tsukada Y I, Fang J, Erdjument-Bromage H. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature, 2006,439: 811-816.
[75] Yamane Toumazou C, Tsukada Y, et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by an drogen receptor. Cell, 2006, 125: 483-495.
[76] Klose R J, Yamane k, Bae Y J, et al. transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature, 2006, 442: 312 - 316.
[77] Wang GG, Allis CD, Chi P. Chromatin remodeling and cancer, Part I: Covalent histone modifications. Trends Mol Med, 2007,13(9): 363-372.
[78] Wang GG, Allis CD, Chi P. Chromatin remodeling and cancer, Part II: ATP- dependent chromatin remodeling. Trends Mol Med. 2007, 13(9): 373-380.
[79] Matzke MA, BircMer JA. RNAi-mediated pathways in the nucleus. Nat Rev Genet, 2005,6: 24-35.
[80] StorzG. An expanding universe of noncoding RNAs. Science, 2002, 296: 1260-1263.
[81] Mattick JS. The functional genomics of noncoding RNA. Science, 2005, 309: 1527-1528.
[82] He L, Th omson JM, Hemann MT, et al. A microRNA polycistron as a potential human oncogene. Nature, 2005, 435: 828-833.
[83] O'Dannell KA, Wentsel EA, Zeller KI, et al. c-Myc-regIllated microRNAs modulate E2FI expression. Nature, 2005,435: 839-843.
[84] Morris JP 4~(th), McManus MT. Slowing down the Ras lane: IniRNAs as tumor suppressors? Sci STKE, 2005,2005: pe41.
[85] Hayeshita Y, Osada H, Tatematsu Y, et al. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancersand enhances cell proliferation. Cancer Res, 2005, 65: 9628-9632.
[86] Cai X, Lu S, Zhang Z, et al. Kaposi's sareoma-associated herpesvirus expresses an array of viral microRNAs in latently infected cells. Proc Nail Acad SCi U S A, 2005,102: 5570-5575.
[87] Wijermans PW, Lubbert M, Verhoef G, et al. An epigenetie approach to the treatment of advanced MDS; the experience with the DNA demethylating agent 5-aza-2'-deoxycytidine(decitabine)in 177 patients. Ann Hematol, 2005, 84 Suppl 1: 9-17.
[88] Kantarjian HM, O'Brien S, Cones J, et al. Results of decitabine (5-aza-2'deoxyeytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer, 2003, 98(3): 522-528.
[89] Link PA, Baer MR, James SR, et al. P53-inducible ribonucleotide reductase (p53R2/RRM2B) is a DNA hypomethylation-independent decitabine gene target that correlates with clinical response in myelodysplastic syndrome/acute myelogenous leukemia. Cancer Res, 2008, 68(22): 9358-9366.
[90] Cheng JC, Yoo CB, Weisenberger DJ, et al. Preferential response of cancer cells to zebularine. Cancer Cell, 2004, 6(2): 151-158.
[91] Winquist E, Knox J, Ayoub JP, et al. Phase II trial of DNA methyhransferase 1 inhibition with the antisense oligonucleotide MG98 in patients with metastatic renal Carcinoma: a National Cancer Institute of Canada Clinical Trials Group investigational new drug study. Invest New Drugs, 2006,24(2): 159-167.
[92] Brueckner B, Boy RG, Siedlecki P, et al. Epigenetie reactivation of tumor suppressor genes by a novel smallmolecule inhibitor of human DNA methyhransferases. Cancer Res, 2005, 65(14): 6305-6311.
[93] Loprevite M, Tiseo M, Grossi F, et al. In vitro study of CI-994. a histone deacetylase inhibitor, in non-small cell lung cancer cell lines. Oncol Res, 2005, 15(1): 39-48.
[94] Villa R, Morey L, Raker VA, et al. The methyl-CpG binding protein MBD1 is required for PML-RARalpha function. Proc Natl Acad Sci USA, 2006, 103 (5): 1400-1405.
[95] Kraimer OH, Muller S, Buchwald M, et al. Mechanism for ubiquitylation of the leukemia fusion proteins AML1-ETO and PML-RARalpha. FASEB J, 2008, 22(5):1369-1379.
[96] Sonnemann J, Kumar KS, Heesch S, et al. Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation, etoposide, and TRAIL in medulloblastoma cells. IntJ Oncol, 2006,28(3): 755-766.
[97] Chen CL, Sung J, Cohen M, et al. Valproic acid inhibits invasiveness in bladder cancer but not in prostate cancer cells. J Pharmacol Exp Ther, 2006, 319(2): 533- 542.
[98] Im JY, Park H, Kang KW, et al. Modulation of cell cycles and apoptosis by apicidin in estrogen receptor(ER)positive and-negative human breast cancer cells. Chem Biol Interact, 2008,172(3): 235-244.
[99] Kim SH, Jeong JW, Park JA, et al. Regulation of the HIF-1alpha stability by histone deacetylases. Oncol Rep, 2007,17(3): 647-651.
[100] Qian DZ, Kachhap SK, Collis SJ, et al. Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alphaIII. Cancer Res, 2006, 66(17): 8814-8821.
[101] Shaker S, Bernstein M, Momparler LF, et al. Preclinical evaluation of antineoplastic activity of inhibitors of DNA methylation (5-aza-2'-deoxycytidine) and histone deacetylation(trichostatin A, depsipeptide)in combination against myeloid leukemic cells. Leuk Res, 2003, 27(5): 437-444.
[102] Zhu WG, Otterson GA. The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. Curr Med Chem Anticancer Agents, 2003,3(3): 187-199.
[103] Yao X, Hu JF, Daniels M, et al. A methylated oligonucleotide inhibits IGF2 expression and enhances survival in a mod el of hepatecellular carcinoma. J Clin lnvest,2003, 111(2): 265-273.
[104] Masiero M, Nardo G, Indraccolo S, et al. RNA interference: implications for cancer treatment.Mol Aspects Med,2007,28(1):143-166.
[105]Aagaard L,Rossi JJ.RNAi therapeutics:principles,prospects and Challenges.Adv Drug Deliv Rev,2007,59(2-3):75-86.
[2]谢爱华,廖晨钟,李伯玉,等.以组蛋白去乙酰化酶为靶标的抗癌药物研发进展.中国新药杂志,2005,14(1):10-14.
[3]林贞花.子宫及卵巢肿瘤病理基础研究中的几点问题.中华病理学杂志,2007,36(8):508-510.
[4]Micha JP,Goldstein BH,Rettenmaier MA,et al.Clinical utility of CA-125 for maintenance therapy in the treatment of advanced stage ovarian carcinoma,lnt J Gynecol Cancer,2009,19(2):239-241.
[5]Kumar S,Bryant CS,Chamala S,et al.Ritonavir blocks AKT signaling,activates apoptosis and inhibits migration and invasion in ovarian cancer cells.Mol Cancer,2009,8(1):26.
[6]Lee YS,Lim KH,Guo X,et al.The cytoplasmic deacetylase HDAC6 is required for efficient oncogenic tumorigenesis.Clin Cancer Res,2008,68(18):7561-7569.
[7]Hildmann C,Wegener D,Riester D,et al.Substrate and inhibitor specificity of class 1 and class 2 histone deacetylases.JBiotechnol,2006,124(1):258-270.
[8]Li H,Wu X.Histone deacetylase inhibitor,Trichostatin A,activates p21WAF1/CIP1 expression through downregulation of c-myc and release of the repression of c-myc from the promoter in human cervical cancer cells.Biochem Biophys Res Commun,2004,324(2):860-867.
[9]Bi G,Jiang G.The molecular mechanism of HDAC inhibitors in anticancer effects.Cell Mol Immunol,2006,3(4):285-290.
[10]Schafer S,Saunders L,Eliseeva E,et al.Phenylalanine-containing hydroxamic acids as selective inhibitors of class lib histone deacetylases(HDACs).Bioorg Med Chem,2008,16(4):2011-2033.
[11]Fischle W,Kiermer V,Dequiedt F,et al.The emerging role of class Ⅱ histone deacetylases.Biochem Cell Biol,2001,79(3):337-348.
[12]Crazzolara R,Johrer K,Johnstone RW,et al.Histone deacetylase inhibitom potently repress CXCR4 chemokine receptor expression and function in acute lymphoblastic leukaemia.Br J Haematol,2002,119(4):965-969.
[13]Choi JH,Kwon HJ,Yoon BI,et al.Expression profile of histone deacetylase 1 in gastric cancer tissues.Jpn J Cancer Res,2001,92(12):1300-1304.
[14]殷红.组蛋白去乙酰化异常与恶性肿瘤.国外医学生理病理科学与临床分册,2003,23(3):238-241.
[15]Hildmann C,Wegener D,Riester D,et al.Substrate and inhibitor specificity of class 1 and class 2 histone deacetylases.JBiotechnol,2006,124(1):258-270.
[16]Schafer S,Saunders L,Eliseeva E,et al.Phenylalanine-containing hydroxamic acids as selective inhibitors of class IIb histone deacetylases(HDACs).Bioorg Med Chem,2008,16(4):2011-2033.
[17]Li H,Wu X.Histone deacetylase inhibitor,Trichostatin A,activates p21WAF1/CIP1 expression through downregulation of c-myc and release of the repression of c-myc from the promoter in human cervical cancer cells.Biochem Biophys Res Commun,2004,324(2):860-867.
[18]Bi G,Jiang G.The molecular mechanism of HDAC inhibitors in anticancer effects.Cell Mol Immunol,2006,3(4):285-290.
[19]Suzuki T,Kouketsu A,Itoh Y,et al.Highly potent and selective histone deacetylase 6 inhibitors designed based on a small-molecular substrate.J Med Chem,2006,49(16):4809-4812.
[20]Iwata A,Riley BE,Johnston JA,et al.HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin.J Biol Chem,2005,280(48):40282-40292.
[21]Bali P,Pranpat M,Bradner J,et al.Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90:a novel basis for antileukemia activity of histone deacetylase inhibitors,d Biol Chem,2005,280(29):26729-26734.
[22]Iwata A,Riley BE,Johnston JA,et al.HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin.J Biol Chem,2005,280(48):40282-40292.
[23]Heltweg B,Deguiedt F,Marshall BL,et al.Subtype selective substrates for histone deacetylases.J Med Chem,2004,47(21):5235-5243.
[24]Matthias P,Youshida M,Khochbin S.HDAC6 a new cellular stress surveillance factor.Cell Cycle,2008,7(1):7-10.
[25]Gao YS,Hubbert CC,Lu J,et al.Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis.Mol Cell Biol,2007,7(24):8637-8647.
[26]Zhang Z,Yamashita H.Toyama T,et al.HDAC6 expression is correlated with better survival in breast cancer.Clin Cancer Res,2004,10(20):6962-6968.
[27]Wu P,Meng L,Wang H,et al.Role of hTERT in apoptosis of cervical cancer induced by histone deacetylase inhibitor.Biochem Biophys Res Commun,2005,335(1):36-44.
[28]Khabele D,Son DS,Parl AK,et al.Rice VM.Drug-induced inactivation or gene silencing of class I histone deacetylases suppresses ovarian cancer cell growth implications for therapy.Cancer Biol Ther,2007,6(5):759-801.
[29]Bazzaro M,Lin Z,Santillan A,et al.Ubiquitin Proteasome System Stress Underlies Synergistic Killing of Ovarian Cancer Cells by Bortezomib and a Novel HDAC6 Inhibitor.Clin Cancer Res,2008,14(22):7340-7347.
[30]韦进钟,林庆华,谢明权,等.组蛋白脱乙酰酶抑制剂apicidin及其类似物的抗原虫与抗肿瘤作用研究进展.中国新药杂志,2005,14(2):146-150.
[31]Han ES,Lin P,Wakabayashi M.Current status on biologic therapies in the treatment of epithelial ovarian cancer.Curr Treat Options Oncol,2009,Epub ahead of print.
[32]Bijman MN,van Berkel MP,Kok M,et al.Inhibition of functional HER family members increases the sensitivity to docetaxel in human ovarian cancer cell lines.Anticancer Drugs,2009,Epub ahead of print.
[33]Yap OW,Bhat G,Liu L,et al.Epigenetic modifications of the Estrogen receptor beta in epithelial ovarian cancer cells.A nticancer Res,2009,29(1):139-144.
[34]Crazzolara R,Johrer K,Johnstone RW,et al.Histone deacetylase inhibitom potently repress CXCR4 chemokine receptor expression and function in acute lymphoblastic leukaemia.Br J Haematol,2002,119(4):965-969.
[35]Shen C,Buck A K,Liu X,et al.Gene silencing by adenovirusdelivered siRNA.FEBS Lelett,2003,539(27):111-114.
[36]Gramil M,Thelen P,Hemmerlein B,et al.Bax inhibitior-1 is overexpressed in prostate cancer and its specific downregulation by RNA interference leads to cell death in human prostate carcinoma cells.Am JPathol,2003,163(2):543-552.
[37]Villa R,Morey L,Raker VA,et al.The methyl-CpG binding protein MBD1 is required for PML-RARalpha function.Proc NatlAcadSci USA,2006,103(5):1400-1405.
[38]Kramer OH,Muller S,Buchwald M,et al.Mechanism for ubiquitylation of the leukemia fusion proteins AML1-ETO and PML-RARalpha.FASEB J,2008,22(5):1369-1379.
[39]Sonnemann J,Kumar KS,Heesch S,et al.Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation,etoposide,and TRAIL in medulloblastoma cells.Int J Oncol,2006,28(3):755-766.
[40]曲巍,王立明,朱有华.组蛋白去乙酰酶抑制剂联合抗癌药物抑制膀胱癌的实验研究.实用医药杂志,2008,25(5):592-594.
[41]李光明,卢启明.HDAC6表达载体转染对胃癌细胞株SGC-7901生物学行为的影响.第四军医大学学报,2008,29(17):1614-1617.
[42]Saji S,Kawakami M,Hayashi S,et al.Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer.Oncogene,2005,24(28):4531-4539.
[43]黄宏,张珍祥,徐永健,等.HDAC1在肺腺癌细胞株A549中的表达及TSA对细胞增殖、凋亡的影响.中国癌症杂志,2003,22(9):922-926.
[44]Boyault C,Sadoul K,Pabion M,et al.HDAC6,at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination.Oncogene,2007,26(37):5468-5476.
[45]Bordoli L,Netsch M,Luthi U,et al.Plant orthologs of p300 / CBP:conservation of a core domain in metazoan p300 / CBP acetyhransferaserelated proteins.Nucleic Acids Res,2001,29:589-597.
[46]Chen G.Wang BB,Li FJ,et al.Enhancive effect of histone deacetylase inhibitor trichostatin A on transfection efficiency of adenovirus in ovarian carcinoma cell line A2780.Ai Zheng,2005,24(10):1196-1200.
[47]陈刚,王蓓蓓,李辅军,等.HDAC抑制剂TSA增强卵巢癌细胞株A2780对腺病毒基因转染效率的体外研究.癌症,2005,24(10):1196-1200.
[48]Kim D H,Rossi J J.Strategies for silencing human disease using RNA interference.Nat Rev Genet,2007,8(3):173-184.
[49]Jiang L,Chen R,Li J,et al.Inhibition of cyclin E expression and cell proliferation by small interfering RNA in breast cancer MCF-7 cell line.Chinese Journal of Cell BiologY,2006,28:188.
[50]Guan H,Xue X,Wang X,et al.siRNA against survivin coupling with epirubicin enhances to induce breast cancer cell MCF-7 to apoptosis.J Sichuan Univ(Med Sci Edi),2006,37(2):221.
[51]孙红,耿利民,杜萍,黄辰.RNA干扰Survivin基因对Hela细胞凋亡及抗肿瘤药物敏感性的影响.第四军医大学学报,2008,29(20):1843-1846.
[52]王毓,刘培淑,毛洪鸾,等.RNA干扰靶向沉默FLIP基因对卵巢癌细胞A2780生物学特性的影响及生长抑制作用.山东大学学报(医学版),2008,46(2):154-158.
[53]张孟贤,韩娜,于世英.RNA干扰沉默HDAC1基因对大肠癌细胞增殖和凋亡的影响.世界华人消化杂志,2008,16(11):1173-1178.
[1]薛京伦.2006.表观遗传学-原理、技术与实践.上海:上海科学技术出版社.
[2]Fraga MF,Ballestar E,Paz MF,et al.2005.Epigenetic differences arise during the lifetime of monozygotic twins.Proceedings of the National Academy of Science of the United States of America,102(30):10604-10609.
[3]Van Speybreeck L.From to epigenesis to epig enetics:the case ofC.H.Waddington.Ann NYAcad Sci,2002,981:7-49.
[4]Bird A.Perceptions of epigenetics.Nature,2007,447(7143):396-398.
[5]Jones PA,Baylin SB.T he fundamental role of epigenetic events in cancer.Nat Rev Genet,2002,3(6):415-428.
[6]Jaenisch R,Bird A.2003.Epigenetic regulation of gene expression:how the genome integrates intrinsic and environmental signals.Nature Reviews Genetics,33(4):245-254.
[7]Feinbeg A P,Tycko B.The history of caltlcer epigenetics.Nat Rev Cancer,2004,4:143-153.
[8]Robertson KD.DNA methylation and human disease.Nat Rev Genel,2005,6:597-610.
[9]Rakyan VK,Hildmann T,Novik KL,et al.DNAmethylation profiling of the human major histocompatibility complex:a pilot study for the human epigenome project.PLoS Biod,2004,2:e405.
[10]张丽丽,吴建新.2006.DNA甲基化-肿瘤产生的一种表观遗传学机制.遗传,28(7):880-885.
[11]Jones PA,Martienssen R.A blueprint for a Human Epigenome Workshop.Cancer Res,2005,65:11241-11246.
[12]Macaluso M,Paggi MG,Giardano A.Genetic and epigenetic alterations as hallmarks of the intrcate road to cancer.Oncogene.2003,22:6472-6478.
[13]Laird PW.The power and the promise of DNA methylation markers.Nat Rev Cancer,2003,3:253-266.
[14]Scanlan MJ,Simpson AJ,Old LJ.The cancer/testis genes:review,standardi zation, and conmmnentary . Cancer Immun, 2004,4:1.
[15] Socko D. How an imprint can lead to cancer, CMA J, 2005,172: 1286.
[16] Callou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic. Diabetes, 2005, 54:1899-1906.
[17] Davis CD, Hord NG. Nutritional "omics" technologies for Elucidating the role(s) of bioactive food components in colon cancer prevention. J Nutr, 2005, 135: 2694-2697.
[18] Pham AD, Sauer F. Ubiquitin-activating/conjugating activity of TAFn250, a mediator of activation of gene expression in Drosophila. Science, 2000, 289: 2357-2360.
[19] Sassone-Corai P, Mizzen CA, Cheung P, et al. Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3. Science, 1999, 285: 886-891.
[20] Nakayama J, Rice JC, Strahl BD, et al. Role of histone H3 lysine 9 methylation in epigenetic control of heterechrematin assembly. Science, 2001,292: 110-113.
[21] Lattal KM, Barrett RM, Wood MA. Systemic or intrahippocampal delivery of histone deacetylase inhibitors facilitates fear extinction. Behav Neurosci, 2007, 121(5): 1125-1131.
[22] Zhao TC, Cheng G, Zhang LX, et al. Inhibition of histone deacetylases triggers pharmacologic preconditioning effects against myocardial ischemic injury. Cardiovasc Res, 2007, 76(3): 473-481.
[23] Rao J, Bhattacharya D, Banerjee B, et al. Trichostatin-A induces differential changes in histone protein dynamics and expression in HeLa cells. Biochem Biophys Res Commun, 2007, 363(2): 263-268.
[24] Mai A, Perrone A, Nebbioso A, et al. Novel uracil-based 2-aminoanilide and 2-aminoanilide-like derivatives: histone deacetylase inhibition and in-cell activities. BioorgMedChem Lett, 2008, 18(8): 2530-2535.
[25] Mizzen CA, Allis CD. Linking histone acetylation to transcriptional regulation. Cell Mol Life Sci, 1998, 54: 6-20.
[26]Mazzarelli P,Pucci S,Bonanno E,et aI.Camitine palmitoyltransferase Ⅰ in man carcinomas:a novel role in histone deacetylation? Cancer Biol Ther,2007,6(10):1606-1613.
[27]Condorelli F,Gnemmi I,Vallario A,et al.Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells.Br J Pharraacol,2008,153(4):657-668.
[28]Gopal YN,Van Dyke MW.Depletion of histone deacetylase protein:a common consequence of inflammatory cytokine signaling? Cell Cycle,2006,5(23):2738-2743.
[29]Lipinski KS,Fax P.W ilker B,et al.Differences in the interactions of oncogenic adenovirus 12 early region 1A and nononcogenic adenovirus 2early region 1 A with the cellular coactivators p300 and CBP.Virology,1999,255:94-105.
[30]Versteege I,Sevenet N,Lange J,et al.Truncating mutations of hSNFS/INI1 in aggressive paediatric cancer.Nature,1998,394:203-206.[31]Giordano A.Avantaggiati ML.p300 and CBP:partners for life and death.J Cell Physiol,1999,181:218-230.
[32]He LZ,Guidez F,Tribioli C,et al.Distinct interactions of PML-RAR a and PLZF-RAR a with co-repressora determine differential resents to RA in APL.Nat Genet.1998,18:126-135.
[33]Lutterbach B,Westendorf JJ,Linggi B,et al.ETO,a target of t(8;21)in acute leukemia,jnteracts with the N-CoR and rosin3 corepressors.Mol Cell Biol,1998,18:7176-7184.
[34]Bordoli L,Netsch M,Luthi U,et al.Plant orthologs of p300/CBP:conservation of a core domain in metazoan p300/CBP acetyhransferaserelated proteins.Nucleic Acids Res,2001,29:589-597.
[35]刘飞,靳飞,翟晓巧,等.组蛋白甲基化和去甲基化研究进展.中国衣业通报,2007,23(2):56-59.
[36]PetersonC L,LanielM A.Histones and hlstone modifications.Ctnr.Biol,2004,14:R546-551.
[37]Malguoron R,Trojor P,Reinberg D.The key to development:interpreting the histone code? Cmr. Opin. Genet. Dev, 2005,15:163-176.
[38] Bannister A J, Schneider R, Kouzarides T. Histone methylation: dynamic or static?Cell, 2002,109: 801-806.
[39] Petr L. A plant dialect of the histone language. Trend in Plant Science, 2004, 9:84-90.
[40] Tschierseh B, Hofmann A, Krauss V, et al. The protein encoded by the Drosophila position-effect variegation suppressor gene Su(var)3-9 combines domains of antagonistic regulators of homeotic gene complexes. EMBO J, 1994,13: 3822-3831.
[41] ReaS, EisenhaberF, BrianD, et al. Regulation of chromatin structlure by sitespecific histone H3 methyltransferases. Nature, 2000,406: 593-599.
[42] Bannister A J, Zegerman P, Partridge J F, et al. Selective recognition Of methyhted lysine 9 on histone H3 by the HP1 chromo domain. Nature, 2001, 410: 120-124.
[43] Fischle W, Wang Y, Jacobs S A, et al. Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomaim. Genes Dov, 2003,17:1870-1881.
[44] Nakayama J, Rice J C, StrahlB D, et al. Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science, 2001, 292:110-113
[45] Peters A H F M, Kubicek S, Mechtlor K, et al. Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol.Cell, 2003, 12: 1577-1589.
[46] Rice J C, Briggs S D, UeberheideB, et al. Histonemethyltramfemses direct diferent degrees of methylation to define distinct chromatin domains. Mol. Cell, 2003,12:1591-1598.
[47] Eissenberg J C, Elgin SC. The HP1 protein family: getting a grip on Chromatin. Curt. Opin. Genet. Dev, 2000, 10: 204-210.
[48] Tachibana M, Ueda J, Fukuda M, et al. Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev, 2005,19: 815-826.
[49] Tachibana M, Sugimoto K, Nozaki M, et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev, 2002,16:1779-1791.
[50] Ayyanathan K, Lechner M S, Bell P, et al. Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing:a mammalian cell culture model of gene variegation. Genes Dev, 2003, 17: 1855-1869.
[51] Elgin S C R, Grewal, S I S. Heterochromatin: silence is golden. Curt. Biol, 2003, 13: R895-898.
[52] Partridge J F, Borgstrom B, Allshire R C. Distinct protein interaction domains and protein spreading in a complex centromere. Genes Dev, 2000, 14: 783-791.
[53] Partridge J F, Scott K S, Bannister A J, et al. Cis-acting DNA from fission yeast centromeres mediates histone H3 methylation and recruitment of silencing factors and cohesin to an ectopic site. Curt. Biol, 2002, 12: R1652-1660.
[54] Verdel A, Jia S, Gerber S, et al. RNAi-mediated targeting of heterochromatin by the RITS complex. Science, 2004, 303: 672-676.
[55] Sugiyama T, Cam H, Verdel, et al. RNA-dependent RNA polymerase is an essential component of a self-enforcing loop coupling heterochromatin assembly to siRNA production. Proc. Natl Acad. Sci, 2005,102: 152-157.
[56] Andreas H, Demidov D, Gernand D, et al. Methylation of histone H3 in euchromatin of plant chromosomes depends on basic nuclear DNAcontent. The Plant Journal, 2003, 33: 967-973.
[57] Briggs S, BrykM, StrahlM D, et al. Histone H3 lysine 4 methylation Is mediated by Setl and required for cell growth and rDNA silencing in Saccharomyees cerevisiae. Genes Dev, 2001,15: 3286-3295.
[58] Santos-Rosa H, Schneider R, Bannister A J. et al. Active genes are trimethylated at K4 ofhistone H3. Nature, 2002, 419: 407-411.
[59] Ng H H, Robert F, Young R A, et al. Targeted recruitment of Setl histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity. Mol Cell, 2003,11: 709-719.
[60] Pray-Grant M G, Daniel J A, Schieltz D, et al. Chdl chromodomain links histone H3 methylation with SAGA-and SLIK-dependent aeetylation. Naturo, 2005, 433: 434-438.
[61] Wysocka J, Swigut T, Mitne T, et al. WDR5 associates with histone H3 methylated at K4 and is essential for H3-K4 methylation and vertebrate development. Cell, 2005,121: 859-872.
[62] Dou Y, Mitne T A, Tacket A J, et al. Physical association and coordinate function of the H3-K4 methyltransferase MLLland the H4 K16 acetyltransferase MOF.Cell, 2005,121:873-885.
[63] Xiao T, Hall H, Kizer K O, et al. Phosphorylation of RNA polymerase II CTD regulates H3 methylation in yeast. Genes Dev, 2003,17: 654663.
[64] Krogan N J, Kim M, Tong A, et al. Methylation of histone H3 by Set2 in Saccharomyces cerevisiae is linked to transcriptional elongation by RNA polymerase II. Mol. Cell. Biol. 2003,23: 4207-4218.
[65] Li B, Howe L, Anderson S, et al. The Set2 histone methyltransferase functions through the phosphorylated carboxyl-terminal domain of RNA polymeras II. J. Biol. Chem, 2003, 278: 8897-8903.
[66] Wysocka J, Milne T A, Allis C D. Taking LSDI to a New High. Cell, 2005, 122: 654-658.
[67] Paik W, Kim S. Enzymatic demethylation of calf thymus histones. Biochem. Biophys. Res. Commun, 1973, 51: 781-788.
[68] Shi Y, Lan F, Matson C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSDI. Cell, 2004,119: 941-953.
[69] Hakimi M, Bochar D A, Chenoweth J, et al.A Cole-BRAF35 comple containing histone deacetylase mediates repression of neuronal-specific genes. Proc. Natl Acad. Sci, 2002, 99: 7420-7425.
[70] Shi Y J, Sawada J I, Sui G, et al. Coordinated histene modifications mediated by a CtBP co-repressor complex. Nature, 2003 422:735-738.
[71] Hakimi M, Dong Y, Lane W S, et al. A candidate X-linked mental Retardation gene is a component of a new family of histone deacetylase-containing complexes. J. Biol. Chem, 2003,278: 7234-7239.
[72] Lee M J, WynderC, CochN, et al. An essential role for CoREST in Nucleosomal histone 3 lysine 4 demethylation. Nature, 2005,437:432-435.
[73] Metzger E, Wissmann M, Yin N, et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature, 2005, 437: 436-439.
[74] Tsukada Y I, Fang J, Erdjument-Bromage H. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature, 2006,439: 811-816.
[75] Yamane Toumazou C, Tsukada Y, et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by an drogen receptor. Cell, 2006, 125: 483-495.
[76] Klose R J, Yamane k, Bae Y J, et al. transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature, 2006, 442: 312 - 316.
[77] Wang GG, Allis CD, Chi P. Chromatin remodeling and cancer, Part I: Covalent histone modifications. Trends Mol Med, 2007,13(9): 363-372.
[78] Wang GG, Allis CD, Chi P. Chromatin remodeling and cancer, Part II: ATP- dependent chromatin remodeling. Trends Mol Med. 2007, 13(9): 373-380.
[79] Matzke MA, BircMer JA. RNAi-mediated pathways in the nucleus. Nat Rev Genet, 2005,6: 24-35.
[80] StorzG. An expanding universe of noncoding RNAs. Science, 2002, 296: 1260-1263.
[81] Mattick JS. The functional genomics of noncoding RNA. Science, 2005, 309: 1527-1528.
[82] He L, Th omson JM, Hemann MT, et al. A microRNA polycistron as a potential human oncogene. Nature, 2005, 435: 828-833.
[83] O'Dannell KA, Wentsel EA, Zeller KI, et al. c-Myc-regIllated microRNAs modulate E2FI expression. Nature, 2005,435: 839-843.
[84] Morris JP 4~(th), McManus MT. Slowing down the Ras lane: IniRNAs as tumor suppressors? Sci STKE, 2005,2005: pe41.
[85] Hayeshita Y, Osada H, Tatematsu Y, et al. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancersand enhances cell proliferation. Cancer Res, 2005, 65: 9628-9632.
[86] Cai X, Lu S, Zhang Z, et al. Kaposi's sareoma-associated herpesvirus expresses an array of viral microRNAs in latently infected cells. Proc Nail Acad SCi U S A, 2005,102: 5570-5575.
[87] Wijermans PW, Lubbert M, Verhoef G, et al. An epigenetie approach to the treatment of advanced MDS; the experience with the DNA demethylating agent 5-aza-2'-deoxycytidine(decitabine)in 177 patients. Ann Hematol, 2005, 84 Suppl 1: 9-17.
[88] Kantarjian HM, O'Brien S, Cones J, et al. Results of decitabine (5-aza-2'deoxyeytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer, 2003, 98(3): 522-528.
[89] Link PA, Baer MR, James SR, et al. P53-inducible ribonucleotide reductase (p53R2/RRM2B) is a DNA hypomethylation-independent decitabine gene target that correlates with clinical response in myelodysplastic syndrome/acute myelogenous leukemia. Cancer Res, 2008, 68(22): 9358-9366.
[90] Cheng JC, Yoo CB, Weisenberger DJ, et al. Preferential response of cancer cells to zebularine. Cancer Cell, 2004, 6(2): 151-158.
[91] Winquist E, Knox J, Ayoub JP, et al. Phase II trial of DNA methyhransferase 1 inhibition with the antisense oligonucleotide MG98 in patients with metastatic renal Carcinoma: a National Cancer Institute of Canada Clinical Trials Group investigational new drug study. Invest New Drugs, 2006,24(2): 159-167.
[92] Brueckner B, Boy RG, Siedlecki P, et al. Epigenetie reactivation of tumor suppressor genes by a novel smallmolecule inhibitor of human DNA methyhransferases. Cancer Res, 2005, 65(14): 6305-6311.
[93] Loprevite M, Tiseo M, Grossi F, et al. In vitro study of CI-994. a histone deacetylase inhibitor, in non-small cell lung cancer cell lines. Oncol Res, 2005, 15(1): 39-48.
[94] Villa R, Morey L, Raker VA, et al. The methyl-CpG binding protein MBD1 is required for PML-RARalpha function. Proc Natl Acad Sci USA, 2006, 103 (5): 1400-1405.
[95] Kraimer OH, Muller S, Buchwald M, et al. Mechanism for ubiquitylation of the leukemia fusion proteins AML1-ETO and PML-RARalpha. FASEB J, 2008, 22(5):1369-1379.
[96] Sonnemann J, Kumar KS, Heesch S, et al. Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation, etoposide, and TRAIL in medulloblastoma cells. IntJ Oncol, 2006,28(3): 755-766.
[97] Chen CL, Sung J, Cohen M, et al. Valproic acid inhibits invasiveness in bladder cancer but not in prostate cancer cells. J Pharmacol Exp Ther, 2006, 319(2): 533- 542.
[98] Im JY, Park H, Kang KW, et al. Modulation of cell cycles and apoptosis by apicidin in estrogen receptor(ER)positive and-negative human breast cancer cells. Chem Biol Interact, 2008,172(3): 235-244.
[99] Kim SH, Jeong JW, Park JA, et al. Regulation of the HIF-1alpha stability by histone deacetylases. Oncol Rep, 2007,17(3): 647-651.
[100] Qian DZ, Kachhap SK, Collis SJ, et al. Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alphaIII. Cancer Res, 2006, 66(17): 8814-8821.
[101] Shaker S, Bernstein M, Momparler LF, et al. Preclinical evaluation of antineoplastic activity of inhibitors of DNA methylation (5-aza-2'-deoxycytidine) and histone deacetylation(trichostatin A, depsipeptide)in combination against myeloid leukemic cells. Leuk Res, 2003, 27(5): 437-444.
[102] Zhu WG, Otterson GA. The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. Curr Med Chem Anticancer Agents, 2003,3(3): 187-199.
[103] Yao X, Hu JF, Daniels M, et al. A methylated oligonucleotide inhibits IGF2 expression and enhances survival in a mod el of hepatecellular carcinoma. J Clin lnvest,2003, 111(2): 265-273.
[104] Masiero M, Nardo G, Indraccolo S, et al. RNA interference: implications for cancer treatment.Mol Aspects Med,2007,28(1):143-166.
[105]Aagaard L,Rossi JJ.RNAi therapeutics:principles,prospects and Challenges.Adv Drug Deliv Rev,2007,59(2-3):75-86.