Derepression of CLDN3 and CLDN4 During Ovarian Tumorigenesis is Associated with Loss of Repressive Histone Modifications

Overview

Journal Carcinogenesis

Specialty Oncology

Date 2010 Jan 8

PMID 20053926

Citations 37

Authors

Mi Jeong Kwon

Sung-Su Kim

Yoon-La Choi

Hun Soon Jung

Curt Balch

Su-Hyeong Kim

Yong-Sang Song

Victor E Marquez

Kenneth P Nephew

Young Kee Shin

Affiliations

Soon will be listed here.

Abstract

Unlike epigenetic silencing of tumor suppressor genes, the role of epigenetic derepression of cancer-promoting genes or oncogenes in carcinogenesis remains less well understood. The tight junction proteins claudin-3 and claudin-4 are frequently overexpressed in ovarian cancer and their overexpression was previously reported to promote the migration and invasion of ovarian epithelial cells. Here, we show that the expression of claudin-3 and claudin-4 is repressed in ovarian epithelial cells in association with promoter 'bivalent' histone modifications, containing both the activating trimethylated histone H3 lysine 4 (H3K4me3) mark and the repressive mark of trimethylated histone H3 lysine 27 (H3K27me3). During ovarian tumorigenesis, derepression of CLDN3 and CLDN4 expression correlates with loss of H3K27me3 in addition to trimethylated histone H4 lysine 20 (H4K20me3), another repressive histone modification. Although CLDN4 repression was accompanied by both DNA hypermethylation and repressive histone modifications, DNA methylation was not required for CLDN3 repression in immortalized ovarian epithelial cells. Moreover, activation of both CLDN3 and CLDN4 in ovarian cancer cells was associated with simultaneous changes in multiple histone modifications, whereas H3K27me3 loss alone was insufficient for their derepression. CLDN4 repression was robustly reversed by combined treatment targeting both DNA demethylation and histone acetylation. Our study strongly suggests that in addition to the well-known chromatin-associated silencing of tumor suppressor genes, epigenetic derepression by the conversely related loss of repressive chromatin modifications also contributes to ovarian tumorigenesis via activation of cancer-promoting genes or candidate oncogenes.

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References

Baylin S, Ohm J . Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction?. Nat Rev Cancer. 2006; 6(2):107-16. DOI: 10.1038/nrc1799. View

Kourmouli N, Jeppesen P, Mahadevhaiah S, Burgoyne P, Wu R, Gilbert D . Heterochromatin and tri-methylated lysine 20 of histone H4 in animals. J Cell Sci. 2004; 117(Pt 12):2491-501. DOI: 10.1242/jcs.01238. View

Vaissiere T, Sawan C, Herceg Z . Epigenetic interplay between histone modifications and DNA methylation in gene silencing. Mutat Res. 2008; 659(1-2):40-8. DOI: 10.1016/j.mrrev.2008.02.004. View

Agarwal R, DSouza T, Morin P . Claudin-3 and claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity. Cancer Res. 2005; 65(16):7378-85. DOI: 10.1158/0008-5472.CAN-05-1036. View

Esteller M . Epigenetics in cancer. N Engl J Med. 2008; 358(11):1148-59. DOI: 10.1056/NEJMra072067. View

Lan F, Nottke A, Shi Y . Mechanisms involved in the regulation of histone lysine demethylases. Curr Opin Cell Biol. 2008; 20(3):316-25. PMC: 2674377. DOI: 10.1016/j.ceb.2008.03.004. View

Guo Z, Hong J, Irvine K, Chen G, Spiess P, Liu Y . De novo induction of a cancer/testis antigen by 5-aza-2'-deoxycytidine augments adoptive immunotherapy in a murine tumor model. Cancer Res. 2006; 66(2):1105-13. PMC: 2242843. DOI: 10.1158/0008-5472.CAN-05-3020. View

Lee E, Murdoch F, Fritsch M . High histone acetylation and decreased polycomb repressive complex 2 member levels regulate gene specific transcriptional changes during early embryonic stem cell differentiation induced by retinoic acid. Stem Cells. 2007; 25(9):2191-9. DOI: 10.1634/stemcells.2007-0203. View

Fuks F . DNA methylation and histone modifications: teaming up to silence genes. Curr Opin Genet Dev. 2005; 15(5):490-5. DOI: 10.1016/j.gde.2005.08.002. View

10.

Issaeva I, Zonis Y, Rozovskaia T, Orlovsky K, Croce C, Nakamura T . Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth. Mol Cell Biol. 2006; 27(5):1889-903. PMC: 1820476. DOI: 10.1128/MCB.01506-06. View

11.

Fischle W, Wang Y, Allis C . Histone and chromatin cross-talk. Curr Opin Cell Biol. 2003; 15(2):172-83. DOI: 10.1016/s0955-0674(03)00013-9. View

12.

Kondo Y, Shen L, Cheng A, Ahmed S, Boumber Y, Charo C . Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat Genet. 2008; 40(6):741-50. DOI: 10.1038/ng.159. View

13.

Shepherd T, Theriault B, Campbell E, Nachtigal M . Primary culture of ovarian surface epithelial cells and ascites-derived ovarian cancer cells from patients. Nat Protoc. 2007; 1(6):2643-9. DOI: 10.1038/nprot.2006.328. View

14.

Sundfeldt K . Cell-cell adhesion in the normal ovary and ovarian tumors of epithelial origin; an exception to the rule. Mol Cell Endocrinol. 2003; 202(1-2):89-96. DOI: 10.1016/s0303-7207(03)00068-6. View

15.

Coral S, Sigalotti L, Colizzi F, Spessotto A, Nardi G, Cortini E . Phenotypic and functional changes of human melanoma xenografts induced by DNA hypomethylation: immunotherapeutic implications. J Cell Physiol. 2005; 207(1):58-66. DOI: 10.1002/jcp.20540. View

16.

Kouzarides T . Chromatin modifications and their function. Cell. 2007; 128(4):693-705. DOI: 10.1016/j.cell.2007.02.005. View

17.

Sakatani T, Kaneda A, Iacobuzio-Donahue C, Carter M, de Boom Witzel S, Okano H . Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science. 2005; 307(5717):1976-8. DOI: 10.1126/science.1108080. View

18.

Fujii S, Ito K, Ito Y, Ochiai A . Enhancer of zeste homologue 2 (EZH2) down-regulates RUNX3 by increasing histone H3 methylation. J Biol Chem. 2008; 283(25):17324-32. PMC: 2427338. DOI: 10.1074/jbc.M800224200. View

19.

Agger K, Cloos P, Christensen J, Pasini D, Rose S, Rappsilber J . UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature. 2007; 449(7163):731-4. DOI: 10.1038/nature06145. View

20.

Yuan X, Lin X, Manorek G, Kanatani I, Cheung L, Rosenblum M . Recombinant CPE fused to tumor necrosis factor targets human ovarian cancer cells expressing the claudin-3 and claudin-4 receptors. Mol Cancer Ther. 2009; 8(7):1906-15. DOI: 10.1158/1535-7163.MCT-09-0106. View