Derepression of CLDN3 and CLDN4 during ovarian tumorigenesis is associated with loss of repressive histone modifications

Mi Jeong Kwon, Sung Su Kim, Yoon La Choi, Hun Soon Jung, Curt Balch, Su Hyeong Kim, Yong Sang Song, Victor E. Marquez, Kenneth Nephew, Young Kee Shin

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)974-983
Number of pages10
JournalCarcinogenesis
Volume31
Issue number6
DOIs
StatePublished - Jan 6 2010

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Histone Code
Histones
Carcinogenesis
Claudin-3
Claudin-4
Epigenomics
Lysine
Neoplasm Genes
Epithelial Cells
Tumor Suppressor Genes
Oncogenes
Ovarian Neoplasms
Chromatin
Tight Junction Proteins
DNA
DNA Methylation
Acetylation

ASJC Scopus subject areas

  • Cancer Research

Cite this

Kwon, M. J., Kim, S. S., Choi, Y. L., Jung, H. S., Balch, C., Kim, S. H., ... Shin, Y. K. (2010). Derepression of CLDN3 and CLDN4 during ovarian tumorigenesis is associated with loss of repressive histone modifications. Carcinogenesis, 31(6), 974-983. https://doi.org/10.1093/carcin/bgp336

Derepression of CLDN3 and CLDN4 during ovarian tumorigenesis is associated with loss of repressive histone modifications. / Kwon, Mi Jeong; Kim, Sung Su; Choi, Yoon La; Jung, Hun Soon; Balch, Curt; Kim, Su Hyeong; Song, Yong Sang; Marquez, Victor E.; Nephew, Kenneth; Shin, Young Kee.

In: Carcinogenesis, Vol. 31, No. 6, 06.01.2010, p. 974-983.

Research output: Contribution to journalArticle

Kwon, MJ, Kim, SS, Choi, YL, Jung, HS, Balch, C, Kim, SH, Song, YS, Marquez, VE, Nephew, K & Shin, YK 2010, 'Derepression of CLDN3 and CLDN4 during ovarian tumorigenesis is associated with loss of repressive histone modifications', Carcinogenesis, vol. 31, no. 6, pp. 974-983. https://doi.org/10.1093/carcin/bgp336
Kwon, Mi Jeong ; Kim, Sung Su ; Choi, Yoon La ; Jung, Hun Soon ; Balch, Curt ; Kim, Su Hyeong ; Song, Yong Sang ; Marquez, Victor E. ; Nephew, Kenneth ; Shin, Young Kee. / Derepression of CLDN3 and CLDN4 during ovarian tumorigenesis is associated with loss of repressive histone modifications. In: Carcinogenesis. 2010 ; Vol. 31, No. 6. pp. 974-983.
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