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

  1. Author:
    Kwon, M. J.
    Kim, S. S.
    Choi, Y. L.
    Jung, H. S.
    Balch, C.
    Kim, S. H.
    Song, Y. S.
    Marquez, V. E.
    Nephew, K. P.
    Shin, Y. K.

  2. Author Address

    [Kwon, Mi Jeong; Kim, Sung-Su; Jung, Hun Soon; Shin, Young Kee] Seoul Natl Univ, Coll Pharm, Dept Pharm, Lab Mol Pathol, Seoul 151742, South Korea. [Choi, Yoon-La] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pathol, Seoul 135710, South Korea. [Balch, Curt; Nephew, Kenneth P.] Indiana Univ, Sch Med, Dept Cellular & Integrat Physiol, Bloomington, IN 47405 USA. [Kim, Su-Hyeong; Song, Yong-Sang] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110744, South Korea. [Song, Yong-Sang] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul 110744, South Korea. [Marquez, Victor E.] NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA.;Shin, YK, Seoul Natl Univ, Coll Pharm, Dept Pharm, Lab Mol Pathol, 599 Gwanak Ro, Seoul 151742, South Korea.;ykeeshin@snu.ac.kr
    1. Year: 2010
    2. Date: Jun
  2. Journal: Carcinogenesis
    1. 31
    2. 6
    3. Pages: 974-983
  4. Type of Article: Article
  5. ISSN: 0143-3334
  1. 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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External Sources

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  2. DOI: 10.1093/carcin/bgp336
  3. View record in Web of Science®
  4. WOS: 000278218500004

Library Notes

  1. Fiscal Year: FY2009-2010
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