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Claudin-4 overexpression is associated with epigenetic derepression in gastric carcinoma

Cited 42 time in Web of Science Cited 45 time in Scopus
Authors
Kwon, Mi Jeong; Kim, Seok-Hyung; Jeong, Hae Min; Jung, Hun Soon; Kim, Sung-Su; Lee, Jae Eun; Gye, Myung Chan; Erkin, Özgür Cem; Koh, Sang Seok; Choi, Yoon-La; Park, Cheol Keun; Shin, Young Kee
Issue Date
2011-11
Publisher
United States and Canadian Academy of Pathology
Citation
Laboratory Investigation; Vol.91(11); pp. 1652-1667
Keywords
claudin-4DNA methylationepigenetic derepressiongastric carcinomahistone modification
Abstract
The tight junction (TJ) protein claudin-4 is aberrantly upregulated in gastric cancer, but its clinical significance and
the molecular mechanisms underlying claudin-4 overexpression in gastric cancer remain unclear. Here, we investigated
its roles and epigenetic mechanisms regulating CLDN4 expression in gastric cancer. We show that increased membranous
expression of claudin-4 in gastric carcinoma is associated with better patient prognosis, whereas cytoplasmic claudin-4
expression did not show a significant association with prognosis. Consistent with the correlation of increased
membranous claudin-4 with favorable clinicopathological factors, claudin-4 overexpression inhibited the migration and
invasion of gastric cancer cells; in contrast, it did not affect cell growth. Claudin-4 expression also increased the barrier
function of TJs. Claudin-4 upregulation was strongly correlated with DNA hypomethylation in both gastric tissues and
gastric cancer cells. Moreover, CLDN4 expression was repressed in normal gastric tissues in association with bivalent
histone modifications, and loss of repressive histone methylations and gain of active histone modifications were
associated with CLDN4 overexpression in gastric cancer cells. Interestingly, CLDN4 repression could be markedly
derepressed by combined treatments that simultaneously target both histone modifications and DNA demethylation in
CLDN4-hypermethylated cells, whereas concomitant changes in histone methylations and acetylations are required
for CLDN4 induction in CLDN4-repressed cells with low DNA methylation. Taken together, this study reveals that
membranous claudin-4 expression is associated with gastric cancer progression and that it is an independent positive
prognosis marker in gastric carcinoma. Furthermore, our findings suggest that epigenetic derepression may be a possible
mechanism underlying CLDN4 overexpression in gastric cancer and that claudin-4 may have potential as a promising
target for the treatment of gastric cancer.
ISSN
0023-6837
Language
English
URI
https://hdl.handle.net/10371/78713
DOI
https://doi.org/10.1038/labinvest.2011.117
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College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Journal Papers (저널논문_약학과)
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