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Cancer Cell International
Published in: Cancer Cell International 1/2008

Open Access 01-12-2008 | Primary research

Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells

Authors: Hideo Watanabe, Kenzo Soejima, Hiroyuki Yasuda, Ichiro Kawada, Ichiro Nakachi, Satoshi Yoda, Katsuhiko Naoki, Akitoshi Ishizaka

Published in: Cancer Cell International | Issue 1/2008

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Abstract

Background

Alterations in the processing of the genetic information in carcinogenesis result from stable genetic mutations or epigenetic modifications. It is becoming clear that nucleosomal histones are central to proper gene expression and that aberrant DNA methylation of genes and histone methylation plays important roles in tumor progression. To date, several histone lysine methyltransferases (HKMTs) have been identified and histone lysine methylation is now considered to be a critical regulator of transcription. However, still relatively little is known about the role of HKMTs in tumorigenesis.

Results

We observed differential HKMT expression in a lung cancer model in which normal human bronchial epithelial (NHBE) cells expressing telomerase, SV40 large T antigen, and Ras were immortal, formed colonies in soft agar, and expressed specific HKMTs for H3 lysine 9 and 27 residues but not for H3 lysine 4 residue. Modifications in the H3 tails affect the binding of proteins to the histone tails and regulate protein function and the position of lysine methylation marks a gene to be either activated or repressed. In the present study, suppression by siRNA of HKMTs (EZH2, G9A, SETDB1 and SUV39H1) that are over-expressed in immortalized and transformed cells lead to reduced cell proliferation and much less anchorage-independent colony growth. We also found that the suppression of H3-K9, G9A and SUV39H1 induced apoptosis and the suppression of H3-K27, EZH2 caused G1 arrest.

Conclusion

Our results indicate the potential of these HKMTs in addition to the other targets for epigenetics such as DNMTs and HDACs to be interesting therapeutic targets.
Appendix
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Literature
1.
Egger G, Liang G, Aparicio A, Jones PA: Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004, 429 (6990): 457-463.CrossRefPubMed
2.
Vogelstein B, Kinzler KW: Cancer genes and the pathways they control. Nat Med. 2004, 10 (8): 789-799.CrossRefPubMed
3.
4.
Allis CD, Berger SL, Cote J, Dent S, Jenuwien T, Kouzarides T, Pillus L, Reinberg D, Shi Y, Shiekhattar R: New nomenclature for chromatin-modifying enzymes. Cell. 2007, 131 (4): 633-636.CrossRefPubMed
5.
Kouzarides T: Histone methylation in transcriptional control. Curr Opin Genet Dev. 2002, 12 (2): 198-209.CrossRefPubMed
6.
Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K: High-resolution profiling of histone methylations in the human genome. Cell. 2007, 129 (4): 823-837.CrossRefPubMed
7.
Martin C, Zhang Y: The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol. 2005, 6 (11): 838-849.CrossRefPubMed
8.
Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M, Yagyu R, Nakamura Y: SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat Cell Biol. 2004, 6 (8): 731-740.CrossRefPubMed
9.
Rea S, Eisenhaber F, O'Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD: Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature. 2000, 406 (6796): 593-599.CrossRefPubMed
10.
Yang L, Xia L, Wu DY, Wang H, Chansky HA, Schubach WH, Hickstein DD, Zhang Y: Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor. Oncogene. 2002, 21 (1): 148-152.CrossRefPubMed
11.
Tachibana M, Sugimoto K, Fukushima T, Shinkai Y: Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J Biol Chem. 2001, 276 (27): 25309-25317.CrossRefPubMed
12.
Su IH, Basavaraj A, Krutchinsky AN, Hobert O, Ullrich A, Chait BT, Tarakhovsky A: Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat Immunol. 2003, 4 (2): 124-131.CrossRefPubMed
13.
Min J, Feng Q, Li Z, Zhang Y, Xu RM: Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Cell. 2003, 112 (5): 711-723.CrossRefPubMed
14.
Baylin SB, Ohm JE: Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction?. Nat Rev Cancer. 2006, 6 (2): 107-116.CrossRefPubMed
15.
Yoo CB, Jones PA: Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov. 2006, 5 (1): 37-50.CrossRefPubMed
16.
17.
Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA: Creation of human tumour cells with defined genetic elements. Nature. 1999, 400 (6743): 464-468.CrossRefPubMed
18.
Soejima K, Fang W, Rollins BJ: DNA methyltransferase 3b contributes to oncogenic transformation induced by SV40T antigen and activated Ras. Oncogene. 2003, 22 (30): 4723-4733.CrossRefPubMed
19.
Davie JK, Dent SY: Histone modifications in corepressor functions. Curr Top Dev Biol. 2004, 59: 145-163.CrossRefPubMed
20.
Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC, Kouzarides T: Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature. 2001, 410 (6824): 120-124.CrossRefPubMed
21.
Lachner M, O'Carroll D, Rea S, Mechtler K, Jenuwein T: Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature. 2001, 410 (6824): 116-120.CrossRefPubMed
22.
Melcher M, Schmid M, Aagaard L, Selenko P, Laible G, Jenuwein T: Structure-function analysis of SUV39H1 reveals a dominant role in heterochromatin organization, chromosome segregation, and mitotic progression. Mol Cell Biol. 2000, 20 (10): 3728-3741.PubMedCentralCrossRefPubMed
23.
Nakayama J, Rice JC, Strahl BD, Allis CD, Grewal SI: Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science. 2001, 292 (5514): 110-113.CrossRefPubMed
24.
Nielsen PR, Nietlispach D, Mott HR, Callaghan J, Bannister A, Kouzarides T, Murzin AG, Murzina NV, Laue ED: Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9. Nature. 2002, 416 (6876): 103-107.CrossRefPubMed
25.
Maison C, Bailly D, Peters AH, Quivy JP, Roche D, Taddei A, Lachner M, Jenuwein T, Almouzni G: Higher-order structure in pericentric heterochromatin involves a distinct pattern of histone modification and an RNA component. Nat Genet. 2002, 30 (3): 329-334.CrossRefPubMed
26.
Yamamoto K, Sonoda M: Self-interaction of heterochromatin protein 1 is required for direct binding to histone methyltransferase, SUV39H1. Biochem Biophys Res Commun. 2003, 301 (2): 287-292.CrossRefPubMed
27.
Montgomery ND, Yee D, Chen A, Kalantry S, Chamberlain SJ, Otte AP, Magnuson T: The murine polycomb group protein Eed is required for global histone H3 lysine-27 methylation. Curr Biol. 2005, 15 (10): 942-947.CrossRefPubMed
28.
Cao R, Zhang Y: The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr Opin Genet Dev. 2004, 14 (2): 155-164.CrossRefPubMed
29.
Erhardt S, Su IH, Schneider R, Barton S, Bannister AJ, Perez-Burgos L, Jenuwein T, Kouzarides T, Tarakhovsky A, Surani MA: Consequences of the depletion of zygotic and embryonic enhancer of zeste 2 during preimplantation mouse development. Development. 2003, 130 (18): 4235-4248.CrossRefPubMed
30.
Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O, Haukaas SA, Salvesen HB, Otte AP, Akslen LA: EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol. 2006, 24 (2): 268-273.CrossRefPubMed
31.
Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP: The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002, 419 (6907): 624-629.CrossRefPubMed
32.
Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF: EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA. 2003, 100 (20): 11606-11611.PubMedCentralCrossRefPubMed
33.
Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K: EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. Embo J. 2003, 22 (20): 5323-5335.PubMedCentralCrossRefPubMed
34.
Jacobs JJ, van Lohuizen M: Polycomb repression: from cellular memory to cellular proliferation and cancer. Biochim Biophys Acta. 2002, 1602 (2): 151-161.PubMed
35.
Tonini T, Bagella L, D'Andrilli G, Claudio PP, Giordano A: Ezh2 reduces the ability of HDAC1-dependent pRb2/p130 transcriptional repression of cyclin A. Oncogene. 2004, 23 (28): 4930-4937.CrossRefPubMed
36.
Tang X, Milyavsky M, Shats I, Erez N, Goldfinger N, Rotter V: Activated p53 suppresses the histone methyltransferase EZH2 gene. Oncogene. 2004, 23 (34): 5759-5769.CrossRefPubMed
37.
Sparmann A, van Lohuizen M: Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006, 6 (11): 846-856.CrossRefPubMed
38.
Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE, Cope L, Mohammad HP, Chen W, Daniel VC, Yu W: A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet. 2007, 39 (2): 237-242.PubMedCentralCrossRefPubMed
39.
Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G, Marth C, Weisenberger DJ, Campan M, Young J, Jacobs I: Epigenetic stem cell signature in cancer. Nat Genet. 2007, 39 (2): 157-158.CrossRefPubMed
40.
Kondo Y, Shen L, Ahmed S, Boumber Y, Sekido Y, Haddad BR, Issa JP: Downregulation of histone H3 lysine 9 methyltransferase G9a induces centrosome disruption and chromosome instability in cancer cells. PLoS ONE. 2008, 3 (4): e2037-PubMedCentralCrossRefPubMed
41.
Atkinson SP, Hoare SF, Glasspool RM, Keith WN: Lack of telomerase gene expression in alternative lengthening of telomere cells is associated with chromatin remodeling of the hTR and hTERT gene promoters. Cancer Res. 2005, 65 (17): 7585-7590.PubMed
42.
Liu C, Fang X, Ge Z, Jalink M, Kyo S, Bjorkholm M, Gruber A, Sjoberg J, Xu D: The telomerase reverse transcriptase (hTERT) gene is a direct target of the histone methyltransferase SMYD3. Cancer Res. 2007, 67 (6): 2626-2631.CrossRefPubMed
43.
Okada Y, Jiang Q, Lemieux M, Jeannotte L, Su L, Zhang Y: Leukaemic transformation by CALM-AF10 involves upregulation of Hoxa5 by hDOT1L. Nat Cell Biol. 2006, 8 (9): 1017-1024.PubMedCentralCrossRefPubMed
44.
Nishioka K, Chuikov S, Sarma K, Erdjument-Bromage H, Allis CD, Tempst P, Reinberg D: Set9, a novel histone H3 methyltransferase that facilitates transcription by precluding histone tail modifications required for heterochromatin formation. Genes Dev. 2002, 16 (4): 479-489.PubMedCentralCrossRefPubMed
45.
Schotta G, Ebert A, Krauss V, Fischer A, Hoffmann J, Rea S, Jenuwein T, Dorn R, Reuter G: Central role of Drosophila SU(VAR)3–9 in histone H3-K9 methylation and heterochromatic gene silencing. Embo J. 2002, 21 (5): 1121-1131.PubMedCentralCrossRefPubMed
Metadata
Title
Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells
Authors
Hideo Watanabe
Kenzo Soejima
Hiroyuki Yasuda
Ichiro Kawada
Ichiro Nakachi
Satoshi Yoda
Katsuhiko Naoki
Akitoshi Ishizaka
Publication date
01-12-2008
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2008
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/1475-2867-8-15

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