Epigenetic modification and cancer

18 1 2006 2 Chinese Bulletin of Life Sciences Vol. 18, No. 1 Feb., 2006 1004-0374(2006)01-0010-05 200001 DNA DNA R730.2; R730.59 A Epigenetic modification and cancer LU Rong, FANG Jing-Yuan* (Shanghai Institute of Digestive Disease, Shanghai Jiaotong University Medical School, Renji Hospital, Shanghai 200001, China) Abstract: Carcinogenesis springs from the combined forces of both genetic and epigenetic events. Although the importance of genetic mutations and deletion in cancer have long been recognized, the role of epigenetic modification including DNA methylation and histone modification has been suggested more recently. An epigenetic event alters the activity of genes without changing their structure. This review focuses on the epigenetic molecular mechanisms involved in cancer onset and progression, and discusses the possibility of new strategies in the development of anticancer treatments. Key words: cancer; epigenetic modification; DNA methylation; histone acetylation 20 70 (Epigenetics) 1 DNA 1942 2005-11-21 (2005CB522400) (1973 ) (1962 ) *

11 (Waddington CH) Epigenetics 1987 (Holiday R) Epigenetics DNA DNA DNA DNA DNA DNA ( H3-K4) ( H3-K9 H3-K27) [1] 2 2.1 DNA DNA [2] DNA DNA (DNA methyltransferase, Dnmt) S- (SAM) (CpG) 5 Dnmt1 Dnmt3a Dnmt3b [3] CpG CpG CpG CpG DNA DNA DNA [4] (CpG ) prb p16 p15 p14 ARF p73 DNA O 6 -MGMT BRCA1 hmlh1 [5] DNA DNA 2.2 DNA ( H3 H4) (H3 7 Lys 2 Ser H4 5 Lys 1 Ser) ADP [6] H3 Lys 9 l4 l8 23 H4 Lys 5 8 12 l6 (histone aceytltransferase HAT) A( CoA) Lys ε- DNA DNA DNA (histone deacetylase HDAC) Lys Lys DNA DNA / HAT( p300/cbp pcaf ACTR ) HDAC

12 Yang [7] E1a p300/cbp p/caf p300/cbp p/caf HAT HDAC TSA ( ) [8] 1991 Mahadevan [9] H3 c-fos c-jun (immediate early, IE) H3 Ser10 [10] ERK- MAPK p38mapk H3 ERK-MAPK c-fos H3 [11] ERK-MAPK H3 H3 ERK-MAPK [12] H3 Ser10 G 2 [13] H3 5 Lys(K4 K9 K27 K36 K79) H4 1 Lys(K20) H3-K9 H3-K27 H4-K20 H3-K4 H3-K36 H3-K79 [14~15] DNA Xin [16] DNA Lehnertz [17]? H3 Lys 3 DNA 1999 CpG [18~20] Schmiemann [21] PCR(methylation-specific real-time PCR QMSP) APC p16(ink4a) RASSF1A QMSP DNA [22~23] [24] DNA DNA Dnmt ( ) (5-aza 5-azadC) (SAH) CpG p14 p15 p16 p21 p53 Rb 5-aza 5-aza-dC Dnmt [25] Dnmt DNA

13 20 90 HDAC HDAC TSA SAHA HDAC [26] HDAC I II SAHA MS-275 CI-994 HDAC HDAC [27] HDAC Dnmt HDAC MLH1 TIMP3 CDKN2B CDKN2A ARHI [28~29] Shaker [30] TSA 5-aza-dC 5-aza-dC HDAC vitamin D 1,25- D [31] 4 (humnan epigenome consortium, HEC) 2003 10 (human epigenome proiect, HEP) DNA (methylation variable positions, MVP) [32] [1] Alvarez-Venegas R, Avramova Z. Methylation patterns of histone H3 Lys 4, Lys 9 and Lys 27 in transcriptionally active and inactive Arabidopsis genes and in atx1 mutants. Nucleic Acids Res, 2005, 33(16):5199~5207 [2] Baylin S B. Tying it all together: epigenetics, genetics, cell cycle and cancer. Science, 1997, 277(5334): 1948~1949 [3] Kanai Y, Ushijima S, Kondo Y, et al. DNA methyltransferase expression and DNA methylation of CpG island and pericentromeric satellite region in human colorectal and stomach cancers. Int J Cancer, 2001, 91(2): 205~212 [4] Tycko B. Epigenetic gene silencing in cancer. J Clin Invest, 2000, 105(4): 401~407 [5] Nephew K P, Huang T H. Epigenetic gene silencing in cancer initiation and progression. Cancer Lett, 2003, 190(2): 125~133 [6] Linggi B E, Brandt S J, Sun Z W, et al. Translating the histone code into leukemia. J Cell Biochem, 2005, 96(5): 938~950 [7] Yang X J, Ogryzko V V, Nishikawa J, et al. A p300/cbpassociated factor that competes with the adenoviral oncoprotein E1A. Nature, 1996, 382(6589): 319~324 [8] 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 [9] Mahadevan L C, Willis A C, Barratt M J. Rapid histone H3 phosphorylation in response to growth factors phorbol esters, okadaic acid, and protein synthesis inhibitors. Cell, 1991, 65(5): 775~783 [10] Nowak S J, Corces V G. Phosphorylation of histone H3: a balancing act between chromosome condensation and transcriptional activation. Trends Genet, 2004, 20(4): 214~220 [11] Salvador L M, Park Y, Cottom J, et al. Follicle-stimulating hormone stimulates protein kinase A-mediated hisone H3 phosphorylation and acetylation leading to select gene activation in ovarian granulosa cell. J Biol Chem, 2001, 276 (43): 40146~40155 [12] Cheung P, Allis C D, Sassone-Corsi P. Signaling to chromatin through histone modifications. Cell, 2000, 103(2): 263~271 [13] Nowak S J, Corces V G. Phosphorylation of histone H3 correlates with transcriptionally active loci. Genes Dev, 2000, 14(23): 3003~3013 [14] Schubeler D, MacAlpine D M, Scalzo D, et al. The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev, 2004, 18(11): 1263~1271 [15] Liang G N, Lin J C, Wei V, et al. Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome. Proc Natl Acad Sci USA, 2004, 101(19): 7357~7362 [16] Xin Z H, Tachibana M, Guggiari M, et al. Role of histone methyltransferase G9a in CpG methylation of the Prader- Willi syndrome imprinting center. J Biol Chem, 2003, 278 (17): 14996~15000 [17] Lehnertz B, Ueda Y, Derijck A A, et al. Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr

14 Biol, 2003, 13(14): 1192~1200 [18] Huang T H, Perry M R, Laux D E. Methylation profiling of CpG islands in human breast cancer cells. Hum Mol Genet, 1999, 8(3): 459~470 [19] Ahluwalia A, Yan P, Hurteau J A, et al. DNA methylation and ovarian cancer. I. Analysis of CpG island hypermethylation in human ovarian cancer using differential methylation hybridization. Gynecol Oncol, 2001, 82(2): 261~268 [20] Yan P S, Shi H D, Rahmatpanah F, et al. Differential distribution of DNA methylation within the RASSF1A CpG island in breast cancer. Cancer Res, 2003, 63(19): 6178~6186 [21] Schmiemann V, Bocking A, Kazimirek M, et al. Methylation assay for the diagnosis of lung cancer on bronchial aspirates: a cohort study. Clin Cancer Res, 2005, 11(21): 7728~7734 [22] Leung W K, To K F, Man E P, et al. Detection of epigenetic changes in fecal DNA as a molecular screening test for colorectal cancer: a feasibility study. Clin Chem, 2004, 50 (11): 2179~2182 [23] Iliopoulos D, Guler G, Han S Y, et al. Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer. Oncogene, 2005, 24(9): 1625~1633 [24] Lyko F, Brown R. DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J Natl Cancer Inst, 2005, 97(20): 1498~1506 [25] Momparler R L. Epigenetic therapy of cancer with 5-aza-2'- deoxycytidine (decitabine). Semin Oncol, 2005, 32(5): 443~451 [26] Marks P A, Jiang X J. Histone deacetylase inhibitors in programmed cell death and cancer therapy. Cell Cycle, 2005, 4(4): 549~551 [27] Somech R, Izraeli S, Simon A J. Histone deacetylase inhibitors a new tool to treat cancer. Cancer Treat Rev, 2004, 30 (5): 461~472 [28] Zhu W G, Lakshmanan R R, Beal M D, et al. DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors. Cancer Res, 2001, 61(4): 1327~1333 [29] Fujii S, Luo R Z, Yuan J, et al. Reactivation of the silenced and imprinted alleles of ARHI is associated with increased histone H3 acetylation and decreased histone H3 lysine 9 methylation. Hum Mol Genet, 2003, 12(15): 1791~1800 [30] Shaker S, Bernstein M, Momparler L F, 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 [31] Rashid S F, Moore J S, Walker E, et al. Synergistic growth inhibition of prostate cancer cells by 1 α, 25 dihydroxyvitamin D(3) and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A. Oncogene, 2001, 20(15): 1860~1872 [32] Bradbury J. Human epigenome project up and running. PLoS Biol, 2003, 1(3): 316~319 2005 G ( ) ( ) ( ) cdna ( ) ( ) 2003 2007 17 23 http: //www.sibs.ac.cn