進階搜尋


下載電子全文  
系統識別號 U0026-1907201111441400
論文名稱(中文) 抑癌基因 FOXO3a 協同組蛋白去乙醯酶進而透過轉錄層次調控 DNA 甲基化轉移酶3B
論文名稱(英文) FOXO3a mediates DNMT3B transcriptional repression by HDAC3
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 99
學期 2
出版年 100
研究生(中文) 楊奕婕
研究生(英文) Yi-Chieh Yang
學號 S26984105
學位類別 碩士
語文別 英文
論文頁數 83頁
口試委員 指導教授-王憶卿
口試委員-賴明德
口試委員-呂增宏
中文關鍵字 甲基化  組蛋白去乙醯酶3  肺癌 
英文關鍵字 DNMT3B  FOXO3a  HDAC3  lung cancer  doxorubicin  nutlin-3 
學科別分類
中文摘要 研究背景及目的: DNA methyltransferase 3B (DNMT3B) 為負責將DNA創造 (de novo) 新甲基化修飾的酵素,目前已知DNMT3B過度表現在腫瘤生成過程中扮演促進的角色。前人研究發現在卵母細胞 (oocyte) 發育過程中,抑癌基因FOXO3a與DNA methyltransferases之轉錄生成物 (transcripts) 的表現量呈現負相關的情形;並且FOXO3a已在肺腺癌 (lung adenocarcinoma) 被報導發現基因缺失。由於DNMT3B過度表現的機制仍不清楚,本研究藉由肺癌細胞模式探討FOXO3a是否會透過轉錄層次抑制DNMT3B基因表現,並且透過臨床肺癌病人檢體以及動物實驗模式觀察FOXO3a與DNMT3B表現量存在負相關的情形。
研究方法及結果:本研究首先透過報導基因冷光酵素活性分析 (luciferase reporter assay) 發現FOXO3a主要透過調控DNMT3B啟動子上蛋白結合位置:FOXO3a-E (+166~+173) 而達到抑制DNMT3B基因的轉錄。另外,以染色質免疫沉澱方法 (chromatin-immuno precipitation PCR) 發現在正常的情況下FOXO3a與HDAC3 (histone deacetylase 3) 會結合至DNMT3B啟動子上含有FOXO3a-E的DNA片段上;然而隨著大量的FOXO3a在細胞核內表現,則會使FOXO3a與HDAC3進一步結合至遠端的 FOXO3a 蛋白結合位置:FOXO3a-P (-249~-242) 的DNA片段;此外,本研究也發現伴隨著FOXO3a結合至啟動子上,會增加H3K27 tri-methylation 並且減少H3K9K14 acetylation修飾作用,使染色質呈現緊密的狀態而不利於基因的轉錄;反之,當細胞內的FOXO3a表現量被抑制表現 (knock down),則HDAC3無法結合至FOXO3a-E位置,使得染色質的結構呈現疏鬆的狀態。進一步,本研究利用免疫沉澱 (immunoprecipitation) 的方法,確定在細胞核內FOXO3a與HDAC3蛋白之間有交互作用,能夠形成一個抑制複合體 (repressive complex),進而協同抑制DNMT3B基因的轉錄。此外,文獻指出MDM2可將FOXO3a進行泛素化 (ubiquitination) 修飾而導致FOXO3a降解。在細胞模式當中,若使用MDM2抑制劑:nutlin-3與促使FOXO3a入核的doxorubicin兩種藥物同時處理細胞,對於DNMT3B基因表現有加成性的抑制作用。本研究進一步以動物實驗證實合併使用nutlin-3以及doxorubicin對於腫瘤生長具有加成性的抑制情形,並且投藥後能透過增加FOXO3a而抑制DNMT3B表現因而達到明顯降低抑癌基因啟動子上DNA 甲基化的程度。在臨床研究上,本研究以免疫組織染色法 (immunohistochemistry) 分析74位非小細胞肺癌病人組織中DNMT3B、FOXO3a以及MDM2表現量之間的關係,發現FOXO3a的表現量與DNMT3B彼此之間存在負相關性(inversely correlation) (P 值為 0.026),FOXO3a與MDM2的表現量也存在負相關性 (P 值為 0.032),另外MDM2與DNMT3B之間則存在正相關 (positively correlation) (P 值為 0.004)。
結論:本研究首先利用細胞模式證實FOXO3a能夠協同HDAC3結合至DNMT3B啟動子上FOXO3a-E位置,並且改變染色質的修飾達到抑制DNMT3B基因轉錄。同時,透過動物實驗的結果,本研究提供一個新穎的nutlin-3以及doxorubicin藥物合併使用作用機制 (透由表遺傳學調控),進一步可以提供新的肺癌藥物治療策略。並且在臨床檢體當中也的確觀察到FOXO3a與DNMT3B存在表達負相關,而MDM2與DNMT3B表達正相關的關係。本研究為第一篇證實FOXO3a透過轉錄層次抑制DNMT3B基因表現的論文。
英文摘要 Background: DNA methyltransferase 3B (DNMT3B) contributes to de novo methylation and its overexpression plays a promoting role in tumorigenesis. However, the mechanisms of DNMT3B overexpression remain unclear. Recent report showed that the expression of FOXO3a, a member of forkhead box class O (FOXO) transcription factors, negatively correlates with expression of DNA methyltransferases during the growth of oocyte. In addition, loss of FOXO3a has been shown to involve in carcinogen-induced lung adenocarcinoma.
Purpose: This study aims to investigate whether FOXO3a transcriptionally represses DNMT3B expression in lung cancer cells. The inverse correlation between FOXO3a and DNMT3B expressions is examined in lung cancer patients and animal models.
Results: According to the luciferase reporter assay, the repressive regulation of FOXO3a was preferentially restricted to the proximal region of DNMT3B promoter, which contains the putative binding site of FOXO3a (+166~+173; FOXO3a-E). In addition, FOXO3a and histone deacetylase HDAC3 bound corporately to the FOXO3a-E site of DNMT3B promoter by chromatin-immunoprecipitation PCR assay. However, when abundant FOXO3a was accumulated in nuclei by doxorubicin treatment, it further bound at the distal putative binding site, FOXO3a-P (-249~-242). Knockdown of FOXO3a resulted in an open chromatin structure evident by a decrease of HDAC3 binding, gain of H3K9K14 acetylation, and loss of H3K27 tri-methylation. In contrast, over-expressed FOXO3a and combined treatment with doxorubicin to induce the FOXO3a nuclear accumulation showed a repressed chromatin structure. Interaction between FOXO3a and HDAC3 proteins was confirmed by immunoprecipitation-Western analysis. Note that FOXO3a is a substrate of MDM2 E3 ligase. Co-treatment with doxorubicin and MDM2 inhibitor, nutlin-3, further enforced abundant nuclear accumulation of FOXO3a to decrease the mRNA level of DNMT3B. In addition, the combined treatment forced the FOXO3a expression and decreased the DNMT3B expression, resulting in additional inhibition of tumor growth and methylation status on tumor suppressor genes in xenograft specimens. Moreover, the inverse correlation between FOXO3a and DNMT3B (P=0.026) and between FOXO3a and MDM2 (P=0.032) and the positive correlation between MDM2 and DNMT3B (P=0.004) were confirmed in tumors from 74 lung cancer patients by immunohistochemistry.
Conclusion: Our studies provide first evidence that FOXO3a transcriptionally represses DNMT3B expression by coordinating binding with HDAC3 to DNMT3B promoter in cell model. This study also shows additional inhibition of antitumor activities for co-treatment of nutlin-3 and doxorubicin in xenograft and provides a new approach for lung cancer therapy. In addition, the clinical data elucidate the inverse correlation between FOXO3a and DNMT3B as well FOXO3a and MDM2, and the positively correlation between DNMT3B and MDM2 in lung cancer patients.
論文目次 CONTENTS
Introduction
I. The epigenetic alteration of cancers
(a) Aberrant promoter DNA methylation of tumor suppressor genes-------------------------------------------------------------------- 1
(b) The functions and structure of DNA methyltransferases (DNMTs)-------------------------------------------------------------- 2
(c) The expression level of DNMTs in cancers----------------------- 5
II. Deregulation of DNMTs in cancer
(a) The studies of promoter methylation status on tumor suppressor genes in our lab------------------------------------------ 6
(b) Carcinogen induces increased protein stability of DNMT1 by post-translational modification--------------------------------- 6
(c) The transcriptional activators of DNMTs------------------------- 7
(d) The transcriptional repressors of DNMTs------------------------- 8
III. Forkhead box O 3a (FOXO3a) in cancer
(a) The expression and role of FOXO3a in cancers------------------ 9
(b) The damage response of FOXO3a--------------------------------- 10
(c) The FOXO3a/MDM2 regulation loop----------------------------- 11
IV. The regulation of gene transcription at chromatin level
(a) Chromatin structure modifications--------------------------------- 12
(b) Histone deacetylases (HDACs)------------------------------------ 13
Purpose----------------------------------------------------------------------- 15
Materials and Methods------------------------------------------------ 17
I. Cell culture------------------------------------------------------------ 17
II. Treatment with doxorubicin and nutlin-3------------------------- 17
III. Plasmid, RNAi and transfection------------------------------------- 17
IV. Dual luciferase assay-------------------------------------------------- 18
V. RNA extraction and quantitative reverse-transcriptase PCR (RT-qPCR) assay----------------------------------------------------- 19
VI. Western blot------------------------------------------------------------ 19
VII. Chromatin immunoprecipitation (ChIP)-PCR assay-------------- 20
VIII. Cell fractionation assay----------------------------------------------- 21
IX. Immunoprecipitation (IP) and Western blot ----------------------- 21
X. Immunofluorescence staining and confocal microscopic analysis------------------------------------------------------------------ 21
XI. Immunohistochemistry (IHC) assay-------------------------------- 22
XII. Xenograft mice experiments----------------------------------------- 23
XIII. Methylation-specific qPCR (q-MSP) for BLU, RASSF1A, and SLIT2 genes------------------------------------------------------------ 24
XIV. Study population------------------------------------------------------- 24
XV. Statistical analysis----------------------------------------------------- 25
Results------------------------------------------------------------------------ 26
In cell models:
I. FOXO3a represses the mRNA and protein expressions of DNMT3B------------------------------------------------------------------- 26
II. FOXO3a negatively regulates the promoter activity of DNMT3B------------------------------------------------------------------- 27
III. FOXO3a binds to region containing its putative binding sites and represses DNMT3B transcription---------------------------------- 28
IV. Binding of FOXO3a changes the chromatin modifications of DNMT3B promoter------------------------------------------------------- 29
V. FOXO3a coordinates with HDAC3 to form a repressive complex and represses DNMT3B expression------------------------------------ 30
VI. Inhibition of MDM2 induces FOXO3a expression and results in decrease of DNMT3B mRNA and protein------------------------- 31
In animal model:
I. Co-treatment with doxorubicin and nutlin-3 diminishes tumor growth---------------------------------------------------------------------- 32
II. Induction of FOXO3a attenuates DNMT3B expression in tumor xenografts from co-treated animals---------------------------- 32
III. The combined treatment reduces the methylation level of TSG promoters----------------------------------------------------------------- 33
In clinical model:
The DNMT3B protein overexpression inversely correlates with the FOXO3a and positively correlates with MDM2 expression in NSCLC patients-------------------------------------------------------- 33
Discussion------------------------------------------------------------------- 35
References------------------------------------------------------------------- 41
Tables--------------------------------------------------------------------------54
Figures------------------------------------------------------------------------ 60
Appendix--------------------------------------------------------------------- 79
參考文獻 Accili, D., and Arden, K.C. (2004). FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117, 421-426.
Acharya, M.R., Sparreboom, A., Venitz, J., and Figg, W.D. (2005). Rational development of histone deacetylase inhibitors as anticancer agents: a review. Mol Pharmacol 68, 917-932.
Ahringer, J. (2000). NuRD and SIN3 histone deacetylase complexes in development. Trends Genet 16, 351-356.
Amara, K., Ziadi, S., Hachana, M., Soltani, N., Korbi, S., and Trimeche, M. (2010). DNA methyltransferase DNMT3b protein overexpression as a prognostic factor in patients with diffuse large B-cell lymphomas. Cancer Sci 101, 1722-1730.
Arden, K.C. (2006). Multiple roles of FOXO transcription factors in mammalian cells point to multiple roles in cancer. Exp Gerontol 41, 709-717.
Askari, M.D., Tsao, M.S., and Schuller, H.M. (2005). The tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone stimulates proliferation of immortalized human pancreatic duct epithelia through beta-adrenergic transactivation of EGF receptors. J Cancer Res Clin Oncol 131, 639-648.
Bakin, A.V., and Curran, T. (1999). Role of DNA 5-methylcytosine transferase in cell transformation by fos. Science 283, 387-390.
Bakker, W.J., Harris, I.S., and Mak, T.W. (2007). FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2. Mol Cell 28, 941-953.
Belinsky, S.A. (2004). Gene-promoter hypermethylation as a biomarker in lung cancer. Nat Rev Cancer 4, 707-717.
Bhaskara, S., Knutson, S.K., Jiang, G., Chandrasekharan, M.B., Wilson, A.J., Zheng, S., Yenamandra, A., Locke, K., Yuan, J.L., Bonine-Summers, A.R., Wells, C. E., Kaiser, J. F., Washington, M. K., Zhao, Z., Wagner, F. F., Sun, Z. W., Xia, F., Holson, E. B., Khabele, D., Hiebert, S. W. (2010). Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 18, 436-447.
Bigey, P., Ramchandani, S., Theberge, J., Araujo, F.D., and Szyf, M. (2000). Transcriptional regulation of the human DNA Methyltransferase (dnmt1) gene. Gene 242, 407-418.
Bird, A. (2002). DNA methylation patterns and epigenetic memory. Genes Dev 16, 6-21.
Blake, D.C., Jr., Mikse, O.R., Freeman, W.M., and Herzog, C.R. (2010). FOXO3a elicits a pro-apoptotic transcription program and cellular response to human lung carcinogen nicotine-derived nitrosaminoketone (NNK). Lung Cancer 67, 37-47.
Borkhardt, A., Repp, R., Haas, O.A., Leis, T., Harbott, J., Kreuder, J., Hammermann, J., Henn, T., and Lampert, F. (1997). Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23). Oncogene 14, 195-202.
Brunet, A., Bonni, A., Zigmond, M.J., Lin, M.Z., Juo, P., Hu, L.S., Anderson, M.J., Arden, K.C., Blenis, J., and Greenberg, M.E. (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857-868.
Budillon, A., Di Gennaro, E., Bruzzese, F., Rocco, M., Manzo, G., and Caraglia, M. (2007). Histone deacetylase inhibitors: a new wave of molecular targeted anticancer agents. Recent Pat Anticancer Drug Discov 2, 119-134.
Callebaut, I., Courvalin, J.C., and Mornon, J.P. (1999). The BAH (bromo-adjacent homology) domain: a link between DNA methylation, replication and transcriptional regulation. FEBS Lett 446, 189-193.
Chang, J.W., Hsu, H.S., Ni, H.J., Chuang, C.T., Hsiung, C.H., Huang, T.H., and Wang, Y.C. (2010). Distinct epigenetic domains separated by a CTCF bound insulator between the tandem genes, BLU and RASSF1A. PLoS One 5, e12847.
Chedin, F., Lieber, M.R., and Hsieh, C.L. (2002). The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a. Proc Natl Acad Sci U S A 99, 16916-16921.
Chen, J.T., Chen, Y.C., Chen, C.Y., and Wang, Y.C. (2001). Loss of p16 and/or pRb protein expression in NSCLC. An immunohistochemical and prognostic study. Lung Cancer 31, 163-170.
Chen, T., and Li, E. (2006). Establishment and maintenance of DNA methylation patterns in mammals. Curr Top Microbiol Immunol 301, 179-201.
Chen, Z.X., Mann, J.R., Hsieh, C.L., Riggs, A.D., and Chedin, F. (2005). Physical and functional interactions between the human DNMT3L protein and members of the de novo methyltransferase family. J Cell Biochem 95, 902-917.
Cheng, X., and Blumenthal, R.M. (2008). Mammalian DNA methyltransferases: a structural perspective. Structure 16, 341-350.
Chuang, L.S., Ian, H.I., Koh, T.W., Ng, H.H., Xu, G., and Li, B.F. (1997). Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. Science 277, 1996-2000.
Costello, J.F., Fruhwald, M.C., Smiraglia, D.J., Rush, L.J., Robertson, G.P., Gao, X., Wright, F.A., Feramisco, J.D., Peltomaki, P., Lang, J.C., et al. (2000). Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet 24, 132-138.
Costello, J.F., and Plass, C. (2001). Methylation matters. J Med Genet 38, 285-303.
Cui, M., Wen, Z., Yang, Z., Chen, J., and Wang, F. (2009). Estrogen regulates DNA methyltransferase 3B expression in Ishikawa endometrial adenocarcinoma cells. Mol Biol Rep 36, 2201-2207.
Davis, R.J., D'Cruz, C.M., Lovell, M.A., Biegel, J.A., and Barr, F.G. (1994). Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma. Cancer Res 54, 2869-2872.
Deng, C., Lu, Q., Zhang, Z., Rao, T., Attwood, J., Yung, R., and Richardson, B. (2003). Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling. Arthritis Rheum 48, 746-756.
Dijkers, P.F., Medema, R.H., Pals, C., Banerji, L., Thomas, N.S., Lam, E.W., Burgering, B.M., Raaijmakers, J.A., Lammers, J.W., Koenderman, L., et al. (2000). Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Mol Cell Biol 20, 9138-9148.
Ehrlich, M. (2003). The ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease. Clin Immunol 109, 17-28.
Emerling, B.M., Weinberg, F., Liu, J.L., Mak, T.W., and Chandel, N.S. (2008). PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a). Proc Natl Acad Sci U S A 105, 2622-2627.
Endo, S., Yamato, K., Hirai, S., Moriwaki, T., Fukuda, K., Suzuki, H., Abei, M., Nakagawa, I., and Hyodo, I. (2011). Potent in vitro and in vivo antitumor effects of MDM2 inhibitor nutlin-3 in gastric cancer cells. Cancer Sci 102, 605-613.
Esteller, M. (2002). CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 21, 5427-5440.
Esteve, P.O., Chang, Y., Samaranayake, M., Upadhyay, A.K., Horton, J.R., Feehery, G.R., Cheng, X., and Pradhan, S. (2011). A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability. Nat Struct Mol Biol 18, 42-48.
Etoh, T., Kanai, Y., Ushijima, S., Nakagawa, T., Nakanishi, Y., Sasako, M., Kitano, S., and Hirohashi, S. (2004). Increased DNA methyltransferase 1 (DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers. Am J Pathol 164, 689-699.
Fabbri, M., Garzon, R., Cimmino, A., Liu, Z., Zanesi, N., Callegari, E., Liu, S., Alder, H., Costinean, S., Fernandez-Cymering, C., et al. (2007). MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci U S A 104, 15805-15810.
Fernandez de Mattos, S., Villalonga, P., Clardy, J., and Lam, E.W. (2008). FOXO3a mediates the cytotoxic effects of cisplatin in colon cancer cells. Mol Cancer Ther 7, 3237-3246.
Finnberg, N., and El-Deiry, W.S. (2004). Activating FOXO3a, NF-kappaB and p53 by targeting IKKs: an effective multi-faceted targeting of the tumor-cell phenotype? Cancer Biol Ther 3, 614-616.
Furukawa-Hibi, Y., Yoshida-Araki, K., Ohta, T., Ikeda, K., and Motoyama, N. (2002). FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress. J Biol Chem 277, 26729-26732.
Galili, N., Davis, R.J., Fredericks, W.J., Mukhopadhyay, S., Rauscher, F.J., 3rd, Emanuel, B.S., Rovera, G., and Barr, F.G. (1993). Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet 5, 230-235.
Gallinari, P., Di Marco, S., Jones, P., Pallaoro, M., and Steinkuhler, C. (2007). HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics. Cell Res 17, 195-211.
Girault, I., Tozlu, S., Lidereau, R., and Bieche, I. (2003). Expression analysis of DNA methyltransferases 1, 3A, and 3B in sporadic breast carcinomas. Clin Cancer Res 9, 4415-4422.
Greer, E.L., and Brunet, A. (2005). FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24, 7410-7425.
Greer, E.L., Oskoui, P.R., Banko, M.R., Maniar, J.M., Gygi, M.P., Gygi, S.P., and Brunet, A. (2007). The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 282, 30107-30119.
Gronbaek, K., Hother, C., and Jones, P.A. (2007). Epigenetic changes in cancer. APMIS 115, 1039-1059.
Hammons, G.J., Yan, Y., Lopatina, N.G., Jin, B., Wise, C., Blann, E.B., Poirier, L.A., Kadlubar, F.F., and Lyn-Cook, B.D. (1999). Increased expression of hepatic DNA methyltransferase in smokers. Cell Biol Toxicol 15, 389-394.
Hecht, S.S. (1999). Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 91, 1194-1210.
Hermann, A., Gowher, H., and Jeltsch, A. (2004). Biochemistry and biology of mammalian DNA methyltransferases. Cell Mol Life Sci 61, 2571-2587.
Hermann, A., Schmitt, S., and Jeltsch, A. (2003). The human Dnmt2 has residual DNA-(cytosine-C5) methyltransferase activity. J Biol Chem 278, 31717-31721.
Herzog, C.R., Blake, D.C., Jr., Mikse, O.R., Grigoryeva, L.S., and Gundermann, E.L. (2009). FoxO3a gene is a target of deletion in mouse lung adenocarcinoma. Oncol Rep 22, 837-843.
Hillion, J., Le Coniat, M., Jonveaux, P., Berger, R., and Bernard, O.A. (1997). AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily. Blood 90, 3714-3719.
Hoffmann, M.J., Engers, R., Florl, A.R., Otte, A.P., Muller, M., and Schulz, W.A. (2007). Expression changes in EZH2, but not in BMI-1, SIRT1, DNMT1 or DNMT3B are associated with DNA methylation changes in prostate cancer. Cancer Biol Ther 6, 1403-1412.
Hsu, H.S., Wang, Y.C., Tseng, R.C., Chang, J.W., Chen, J.T., Shih, C.M., and Chen, C.Y. (2004). 5' cytosine-phospho-guanine island methylation is responsible for p14ARF inactivation and inversely correlates with p53 overexpression in resected non-small cell lung cancer. Clin Cancer Res 10, 4734-4741.
Hu, M.C., Lee, D.F., Xia, W., Golfman, L.S., Ou-Yang, F., Yang, J.Y., Zou, Y., Bao, S., Hanada, N., Saso, H., et al. (2004). IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117, 225-237.
Huang, Y., Myers, S.J., and Dingledine, R. (1999). Transcriptional repression by REST: recruitment of Sin3A and histone deacetylase to neuronal genes. Nat Neurosci 2, 867-872.
Hui, R.C., Francis, R.E., Guest, S.K., Costa, J.R., Gomes, A.R., Myatt, S.S., Brosens, J.J., and Lam, E.W. (2008). Doxorubicin activates FOXO3a to induce the expression of multidrug resistance gene ABCB1 (MDR1) in K562 leukemic cells. Mol Cancer Ther 7, 670-678.
Hutt, J.A., Vuillemenot, B.R., Barr, E.B., Grimes, M.J., Hahn, F.F., Hobbs, C.H., March, T.H., Gigliotti, A.P., Seilkop, S.K., Finch, G.L., et al. (2005). Life-span inhalation exposure to mainstream cigarette smoke induces lung cancer in B6C3F1 mice through genetic and epigenetic pathways. Carcinogenesis 26, 1999-2009.
Jeltsch, A., Nellen, W., and Lyko, F. (2006). Two substrates are better than one: dual specificities for Dnmt2 methyltransferases. Trends Biochem Sci 31, 306-308.
Jinawath, A., Miyake, S., Yanagisawa, Y., Akiyama, Y., and Yuasa, Y. (2005). Transcriptional regulation of the human DNA methyltransferase 3A and 3B genes by Sp3 and Sp1 zinc finger proteins. Biochem J 385, 557-564.
Jones, P.L., and Shi, Y.B. (2003). N-CoR-HDAC corepressor complexes: roles in transcriptional regulation by nuclear hormone receptors. Curr Top Microbiol Immunol 274, 237-268.
Jonsson, H., and Peng, S.L. (2005). Forkhead transcription factors in immunology. Cell Mol Life Sci 62, 397-409.
Kaestner, K.H., Knochel, W., and Martinez, D.E. (2000). Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev 14, 142-146.
Kim, D.H., Kim, J.S., Ji, Y.I., Shim, Y.M., Kim, H., Han, J., and Park, J. (2003). Hypermethylation of RASSF1A promoter is associated with the age at starting smoking and a poor prognosis in primary non-small cell lung cancer. Cancer Res 63, 3743-3746.
Kim, J.S., Kim, H., Shim, Y.M., Han, J., Park, J., and Kim, D.H. (2004). Aberrant methylation of the FHIT gene in chronic smokers with early stage squamous cell carcinoma of the lung. Carcinogenesis 25, 2165-2171.
Kimura, H., Nakamura, T., Ogawa, T., Tanaka, S., and Shiota, K. (2003). Transcription of mouse DNA methyltransferase 1 (Dnmt1) is regulated by both E2F-Rb-HDAC-dependent and -independent pathways. Nucleic Acids Res 31, 3101-3113.
Kim, H., Kwon, Y.M., Kim, J.S., Han, J., Shim, Y.M., Park, J., and Kim, D.H. (2006). Elevated mRNA levels of DNA methyltransferase-1 as an independent prognostic factor in primary nonsmall cell lung cancer. Cancer 107, 1042-1049.
Kishikawa, S., Murata, T., Kimura, H., Shiota, K., and Yokoyama, K.K. (2002). Regulation of transcription of the Dnmt1 gene by Sp1 and Sp3 zinc finger proteins. Eur J Biochem 269, 2961-2970.
Kong, W., He, L., Coppola, M., Guo, J., Esposito, N.N., Coppola, D., and Cheng, J.Q. (2010). MicroRNA-155 regulates cell survival, growth, and chemosensitivity by targeting FOXO3a in breast cancer. J Biol Chem 285, 17869-17879.
Kops, G.J., Dansen, T.B., Polderman, P.E., Saarloos, I., Wirtz, K.W., Coffer, P.J., Huang, T.T., Bos, J.L., Medema, R.H., and Burgering, B.M. (2002). Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419, 316-321.
Kouzarides, T. (2007). Chromatin modifications and their function. Cell 128, 693-705.
Laag, E., Majidi, M., Cekanova, M., Masi, T., Takahashi, T., and Schuller, H.M. (2006). NNK activates ERK1/2 and CREB/ATF-1 via beta-1-AR and EGFR signaling in human lung adenocarcinoma and small airway epithelial cells. Int J Cancer 119, 1547-1552.
Laird, P.W. (2005). Cancer epigenetics. Hum Mol Genet 14 Spec No 1, R65-76.
Lee, J.H., Voo, K.S., and Skalnik, D.G. (2001). Identification and characterization of the DNA binding domain of CpG-binding protein. J Biol Chem 276, 44669-44676.
Lee, M.N., Tseng, R.C., Hsu, H.S., Chen, J.Y., Tzao, C., Ho, W.L., and Wang, Y.C. (2007). Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer. Clin Cancer Res 13, 832-838.
Lees-Murdock, D.J., Lau, H.T., Castrillon, D.H., De Felici, M., and Walsh, C.P. (2008). DNA methyltransferase loading, but not de novo methylation, is an oocyte-autonomous process stimulated by SCF signalling. Dev Biol 321, 238-250.
Lessard, J.A., and Crabtree, G.R. (2010). Chromatin regulatory mechanisms in pluripotency. Annu Rev Cell Dev Biol 26, 503-532.
Li, B., Carey, M., and Workman, J.L. (2007). The role of chromatin during transcription. Cell 128, 707-719.
Li, E., Bestor, T.H., and Jaenisch, R. (1992). Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915-926.
Lin, R.K., Hsieh, Y.S., Lin, P., Hsu, H.S., Chen, C.Y., Tang, Y.A., Lee, C.F., and Wang, Y.C. (2010a). The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients. J Clin Invest 120, 521-532.
Lin, R.K., Hsu, H.S., Chang, J.W., Chen, C.Y., Chen, J.T., and Wang, Y.C. (2007). Alteration of DNA methyltransferases contributes to 5'CpG methylation and poor prognosis in lung cancer. Lung Cancer 55, 205-213.
Lin, R.K., Wu, C.Y., Chang, J.W., Juan, L.J., Hsu, H.S., Chen, C.Y., Lu, Y.Y., Tang, Y.A., Yang, Y.C., Yang, P.C., et al. (2010b). Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer. Cancer Res 70, 5807-5817.
Lin, T.S., Lee, H., Chen, R.A., Ho, M.L., Lin, C.Y., Chen, Y.H., Tsai, Y.Y., Chou, M.C., and Cheng, Y.W. (2005). An association of DNMT3b protein expression with P16INK4a promoter hypermethylation in non-smoking female lung cancer with human papillomavirus infection. Cancer Lett 226, 77-84.
Liu, Y., Oakeley, E.J., Sun, L., and Jost, J.P. (1998). Multiple domains are involved in the targeting of the mouse DNA methyltransferase to the DNA replication foci. Nucleic Acids Res 26, 1038-1045.
Luger, K., Mader, A.W., Richmond, R.K., Sargent, D.F., and Richmond, T.J. (1997). Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389, 251-260.
Luo, R.X., and Dean, D.C. (1999). Chromatin remodeling and transcriptional regulation. J Natl Cancer Inst 91, 1288-1294.
Marsit, C.J., Karagas, M.R., Danaee, H., Liu, M., Andrew, A., Schned, A., Nelson, H.H., and Kelsey, K.T. (2006). Carcinogen exposure and gene promoter hypermethylation in bladder cancer. Carcinogenesis 27, 112-116.
McCabe, M.T., Davis, J.N., and Day, M.L. (2005). Regulation of DNA methyltransferase 1 by the pRb/E2F1 pathway. Cancer Res 65, 3624-3632.
McCabe, M.T., Low, J.A., Imperiale, M.J., and Day, M.L. (2006). Human polyomavirus BKV transcriptionally activates DNA methyltransferase 1 through the pRb/E2F pathway. Oncogene 25, 2727-2735.
Medema, R.H., Kops, G.J., Bos, J.L., and Burgering, B.M. (2000). AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782-787.
Mei, C., Sun, L., Liu, Y., Yang, Y., Cai, X., Liu, M., Yao, W., Wang, C., Li, X., Wang, L., et al. (2010). Transcriptional and post-transcriptional control of DNA methyltransferase 3B is regulated by phosphatidylinositol 3 kinase/Akt pathway in human hepatocellular carcinoma cell lines. J Cell Biochem 111, 158-167.
Michan, S., and Sinclair, D. (2007). Sirtuins in mammals: insights into their biological function. Biochem J 404, 1-13.
Mikse, O.R., Blake, D.C., Jr., Jones, N.R., Sun, Y.W., Amin, S., Gallagher, C.J., Lazarus, P., Weisz, J., and Herzog, C.R. (2010). FOXO3 encodes a carcinogen-activated transcription factor frequently deleted in early-stage lung adenocarcinoma. Cancer Res 70, 6205-6215.
Modur, V., Nagarajan, R., Evers, B.M., and Milbrandt, J. (2002). FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J Biol Chem 277, 47928-47937.
Momparler, R.L. (2003). Cancer epigenetics. Oncogene 22, 6479-6483.
Mortusewicz, O., Schermelleh, L., Walter, J., Cardoso, M.C., and Leonhardt, H. (2005). Recruitment of DNA methyltransferase I to DNA repair sites. Proc Natl Acad Sci U S A 102, 8905-8909.
Motta, M.C., Divecha, N., Lemieux, M., Kamel, C., Chen, D., Gu, W., Bultsma, Y., McBurney, M., and Guarente, L. (2004). Mammalian SIRT1 represses forkhead transcription factors. Cell 116, 551-563.
Nakagawa, H., Nuovo, G.J., Zervos, E.E., Martin, E.W., Jr., Salovaara, R., Aaltonen, L.A., and de la Chapelle, A. (2001). Age-related hypermethylation of the 5' region of MLH1 in normal colonic mucosa is associated with microsatellite-unstable colorectal cancer development. Cancer Res 61, 6991-6995.
Nakagawa, T., Kanai, Y., Saito, Y., Kitamura, T., Kakizoe, T., and Hirohashi, S. (2003). Increased DNA methyltransferase 1 protein expression in human transitional cell carcinoma of the bladder. J Urol 170, 2463-2466.
Nakamura, N., Ramaswamy, S., Vazquez, F., Signoretti, S., Loda, M., and Sellers, W.R. (2000). Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Mol Cell Biol 20, 8969-8982.
Nosho, K., Shima, K., Irahara, N., Kure, S., Baba, Y., Kirkner, G.J., Chen, L., Gokhale, S., Hazra, A., Spiegelman, D., et al. (2009). DNMT3B expression might contribute to CpG island methylator phenotype in colorectal cancer. Clin Cancer Res 15, 3663-3671.
Oka, M., Meacham, A.M., Hamazaki, T., Rodic, N., Chang, L.J., and Terada, N. (2005). De novo DNA methyltransferases Dnmt3a and Dnmt3b primarily mediate the cytotoxic effect of 5-aza-2'-deoxycytidine. Oncogene 24, 3091-3099.
Okano, M., Bell, D.W., Haber, D.A., and Li, E. (1999). DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247-257.
Okano, M., Xie, S., and Li, E. (1998). Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 19, 219-220.
Onuma, H., Vander Kooi, B.T., Boustead, J.N., Oeser, J.K., and O'Brien, R.M. (2006). Correlation between FOXO1a (FKHR) and FOXO3a (FKHRL1) binding and the inhibition of basal glucose-6-phosphatase catalytic subunit gene transcription by insulin. Mol Endocrinol 20, 2831-2847.
Ostler, K.R., Davis, E.M., Payne, S.L., Gosalia, B.B., Exposito-Cespedes, J., Le Beau, M.M., and Godley, L.A. (2007). Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins. Oncogene 26, 5553-5563.
Paik, J.H., Kollipara, R., Chu, G., Ji, H., Xiao, Y., Ding, Z., Miao, L., Tothova, Z., Horner, J.W., Carrasco, D.R., et al. (2007). FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128, 309-323.
Palmisano, W.A., Divine, K.K., Saccomanno, G., Gilliland, F.D., Baylin, S.B., Herman, J.G., and Belinsky, S.A. (2000). Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res 60, 5954-5958.
Patra, S.K., Patra, A., Zhao, H., and Dahiya, R. (2002). DNA methyltransferase and demethylase in human prostate cancer. Mol Carcinog 33, 163-171.
Peterson, E.J., Bogler, O., and Taylor, S.M. (2003). p53-mediated repression of DNA methyltransferase 1 expression by specific DNA binding. Cancer Res 63, 6579-6582.
Pierrou, S., Hellqvist, M., Samuelsson, L., Enerback, S., and Carlsson, P. (1994). Cloning and characterization of seven human forkhead proteins: binding site specificity and DNA bending. EMBO J 13, 5002-5012.
Potente, M., Urbich, C., Sasaki, K., Hofmann, W.K., Heeschen, C., Aicher, A., Kollipara, R., DePinho, R.A., Zeiher, A.M., and Dimmeler, S. (2005). Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J Clin Invest 115, 2382-2392.
Pulling, L.C., Klinge, D.M., and Belinsky, S.A. (2001). p16INK4a and beta-catenin alterations in rat liver tumors induced by NNK. Carcinogenesis 22, 461-466.
Qu, Y., Mu, G., Wu, Y., Dai, X., Zhou, F., Xu, X., Wang, Y., and Wei, F. (2010). Overexpression of DNA methyltransferases 1, 3a, and 3b significantly correlates with retinoblastoma tumorigenesis. Am J Clin Pathol 134, 826-834.
Ren, W., Korchin, B., Lahat, G., Wei, C., Bolshakov, S., Nguyen, T., Merritt, W., Dicker, A., Lazar, A., Sood, A., et al. (2008). Combined vascular endothelial growth factor receptor/epidermal growth factor receptor blockade with chemotherapy for treatment of local, uterine, and metastatic soft tissue sarcoma. Clin Cancer Res 14, 5466-5475.
Robertson, K.D. (2001). DNA methylation, methyltransferases, and cancer. Oncogene 20, 3139-3155.
Robertson, K.D., and Jones, P.A. (2000). DNA methylation: past, present and future directions. Carcinogenesis 21, 461-467.
Saito, Y., Kanai, Y., Sakamoto, M., Saito, H., Ishii, H., and Hirohashi, S. (2001). Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis. Hepatology 33, 561-568.
Saito, Y., Kanai, Y., Nakagawa, T., Sakamoto, M., Saito, H., Ishii, H., and Hirohashi, S. (2003). Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas. Int J Cancer 105, 527-532.
Schmidt, M., Fernandez de Mattos, S., van der Horst, A., Klompmaker, R., Kops, G.J., Lam, E.W., Burgering, B.M., and Medema, R.H. (2002). Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol Cell Biol 22, 7842-7852.
Siedlecki, P., and Zielenkiewicz, P. (2006). Mammalian DNA methyltransferases. Acta Biochim Pol 53, 245-256.
Stahl, M., Dijkers, P.F., Kops, G.J., Lens, S.M., Coffer, P.J., Burgering, B.M., and Medema, R.H. (2002). The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol 168, 5024-5031.
Su, X., Lv, C., Qiao, F., Qiu, X., Huang, W., Wu, Q., Zhao, Z., and Fan, H. (2010). Expression pattern and clinical significance of DNA methyltransferase 3B variants in gastric carcinoma. Oncol Rep 23, 819-826.
Sun, L., Zhao, H., Xu, Z., Liu, Q., Liang, Y., Wang, L., Cai, X., Zhang, L., Hu, L., Wang, G., et al. (2007). Phosphatidylinositol 3-kinase/protein kinase B pathway stabilizes DNA methyltransferase I protein and maintains DNA methylation. Cell Signal 19, 2255-2263.
Sunters, A., Fernandez de Mattos, S., Stahl, M., Brosens, J.J., Zoumpoulidou, G., Saunders, C.A., Coffer, P.J., Medema, R.H., Coombes, R.C., and Lam, E.W. (2003). FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J Biol Chem 278, 49795-49805.
Toyooka, S., Maruyama, R., Toyooka, K.O., McLerran, D., Feng, Z., Fukuyama, Y., Virmani, A.K., Zochbauer-Muller, S., Tsukuda, K., Sugio, K., et al. (2003). Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer. Int J Cancer 103, 153-160.
Tran, H., Brunet, A., Grenier, J.M., Datta, S.R., Fornace, A.J., Jr., DiStefano, P.S., Chiang, L.W., and Greenberg, M.E. (2002). DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296, 530-534.
Tsai, K.L., Sun, Y.J., Huang, C.Y., Yang, J.Y., Hung, M.C., and Hsiao, C.D. (2007). Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification. Nucleic Acids Res 35, 6984-6994.
Tsai, W.B., Chung, Y.M., Takahashi, Y., Xu, Z., and Hu, M.C. (2008). Functional interaction between FOXO3a and ATM regulates DNA damage response. Nat Cell Biol 10, 460-467.
Tseng, R.C., Hsieh, F.J., Shih, C.M., Hsu, H.S., Chen, C.Y., and Wang, Y.C. (2009). Lung cancer susceptibility and prognosis associated with polymorphisms in the nonhomologous end-joining pathway genes: a multiple genotype-phenotype study. Cancer 115, 2939-2948.
Tseng, R.C., Lin, R.K., Wen, C.K., Tseng, C., Hsu, H.S., Hsu, W.H., and Wang, Y.C. (2008). Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type beta-catenin nuclear accumulation in lung tumorigenesis. Oncogene 27, 4488-4496.
Tsurutani, J., Castillo, S.S., Brognard, J., Granville, C.A., Zhang, C., Gills, J.J., Sayyah, J., and Dennis, P.A. (2005). Tobacco components stimulate Akt-dependent proliferation and NFkappaB-dependent survival in lung cancer cells. Carcinogenesis 26, 1182-1195.
Tzao, C., Tsai, H.Y., Chen, J.T., Chen, C.Y., and Wang, Y.C. (2004). 5'CpG island hypermethylation and aberrant transcript splicing both contribute to the inactivation of the FHIT gene in resected non-small cell lung cancer. Eur J Cancer 40, 2175-2183.
Vassilev, L.T., Vu, B.T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004). In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844-848.
Vogt, P.K., Jiang, H., and Aoki, M. (2005). Triple layer control: phosphorylation, acetylation and ubiquitination of FOXO proteins. Cell Cycle 4, 908-913.
Vuillemenot, B.R., Hutt, J.A., and Belinsky, S.A. (2006). Gene promoter hypermethylation in mouse lung tumors. Mol Cancer Res 4, 267-273.
Wang, F., Marshall, C.B., Li, G.Y., Yamamoto, K., Mak, T.W., and Ikura, M. (2009). Synergistic interplay between promoter recognition and CBP/p300 coactivator recruitment by FOXO3a. ACS Chem Biol 4, 1017-1027.
Wang, K., and Li, P.F. (2010). Foxo3a regulates apoptosis by negatively targeting miR-21. J Biol Chem 285, 16958-16966.
Wang, Y.C., Hsu, H.S., Chen, T.P., and Chen, J.T. (2006). Molecular diagnostic markers for lung cancer in sputum and plasma. Ann N Y Acad Sci 1075, 179-184.
Wang, Y.C., Lu, Y.P., Tseng, R.C., Lin, R.K., Chang, J.W., Chen, J.T., Shih, C.M., and Chen, C.Y. (2003). Inactivation of hMLH1 and hMSH2 by promoter methylation in primary non-small cell lung tumors and matched sputum samples. J Clin Invest 111, 887-895.
Weng, S.C., Kashida, Y., Kulp, S.K., Wang, D., Brueggemeier, R.W., Shapiro, C.L., and Chen, C.S. (2008). Sensitizing estrogen receptor-negative breast cancer cells to tamoxifen with OSU-03012, a novel celecoxib-derived phosphoinositide-dependent protein kinase-1/Akt signaling inhibitor. Mol Cancer Ther 7, 800-808.
Wu, C.Y., Tseng, R.C., Hsu, H.S., Wang, Y.C., and Hsu, M.T. (2009). Frequent down-regulation of hRAB37 in metastatic tumor by genetic and epigenetic mechanisms in lung cancer. Lung Cancer 63, 360-367.
Xiao, Y., Word, B., Starlard-Davenport, A., Haefele, A., Lyn-Cook, B.D., and Hammons, G. (2008). Age and gender affect DNMT3a and DNMT3b expression in human liver. Cell Biol Toxicol 24, 265-272.
Xu, W.S., Parmigiani, R.B., and Marks, P.A. (2007). Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26, 5541-5552.
Yanaihara, N., Caplen, N., Bowman, E., Seike, M., Kumamoto, K., Yi, M., Stephens, R.M., Okamoto, A., Yokota, J., Tanaka, T., et al. (2006). Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9, 189-198.
Yang, J.Y., Xia, W., and Hu, M.C. (2006). Ionizing radiation activates expression of FOXO3a, Fas ligand, and Bim, and induces cell apoptosis. Int J Oncol 29, 643-648.
Yang, J.Y., Zong, C.S., Xia, W., Yamaguchi, H., Ding, Q., Xie, X., Lang, J.Y., Lai, C.C., Chang, C.J., Huang, W.C., et al. (2008). ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol 10, 138-148.
Yun, M., Wu, J., Workman, J.L., and Li, B. (2011). Readers of histone modifications. Cell Res.
Zhang, L., Hannay, J.A., Liu, J., Das, P., Zhan, M., Nguyen, T., Hicklin, D.J., Yu, D., Pollock, R.E., and Lev, D. (2006). Vascular endothelial growth factor overexpression by soft tissue sarcoma cells: implications for tumor growth, metastasis, and chemoresistance. Cancer Res 66, 8770-8778.
Zhang, L., Yu, D., Hicklin, D.J., Hannay, J.A., Ellis, L.M., and Pollock, R.E. (2002). Combined anti-fetal liver kinase 1 monoclonal antibody and continuous low-dose doxorubicin inhibits angiogenesis and growth of human soft tissue sarcoma xenografts by induction of endothelial cell apoptosis. Cancer Res 62, 2034-2042.
Zimmermann, C., Guhl, E., and Graessmann, A. (1997). Mouse DNA methyltransferase (MTase) deletion mutants that retain the catalytic domain display neither de novo nor maintenance methylation activity in vivo. Biol Chem 378, 393-405.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2013-08-03起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2013-08-03起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw