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

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.

Expression of claudin-3 and claudin-4 in gastric adenocarcinomas and precursor lesions

“…However, expression of claudin-3 and claudin-4 was significantly weaker for cases with positive lymphatic invasion. It is suggested that claudin-3 and claudin-4 may be involved as important proteins during the lymphatic invasion process in gastric cancer, which is consistent with the results obtained by Jung et al(2011) for both claudins, and also those of Kwon et al (2011), who found a significant inverse correlation of claudin-4 expression with tumor invasion and metastasis. Relatively few studies have examined the expression levels of claudin-3 and claudin-4 in precursor lesions.…”

Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants

“…Increased expression of CLDN4 on the membrane enhances the barrier like function of tight junctions which tends to prevent the migration and invasion of gastric cancer cells, without affecting cell growth. The epigenetic regulation of CLDN4 overexpression and its clinical significance as potential therapeutic targets was reported by Kwon et al [19] . DNA hypomethylation parallels to CLDN4 upregulation in both cancerous and non-cancerous gastric tissues.…”

“…DNA hypomethylation parallels to CLDN4 upregulation in both cancerous and non-cancerous gastric tissues. In normal gastric tissues, bivalent histone modifications often lead to repression of CLDN4 expression, whereas loss of repressive histone methylations results in upregulation of CLDN4 in gastric cancer cells [19] . Methylation level of long interspersed element-1 (LINE-1) is associated with esophagus gastric as well as colon cancer progression and prognosis [20] ; this helps in assessing tumor heterogeneity and drug efficacy for the personalized treatment of patients with gastrointestinal cancers.…”

Expression Pattern and Prognostic Significance of Claudin 1, 4 and 7 in Pancreatic Cancer

“…Claudin 1,4 and 7 are important members of this Claudin protein family and their expressions show alterations in many different malignancies such as oesophageal, gastric, biliary (Usami et al, 2006;Agarwal et al, 2009;Kwon et al, 2011), ovarian (Kwon et al, 2010), endometrial (Pan et al, 2007;Knoecny et al, 2008), bladder (Boireau et al, 2007;Szekely et al, 2011) renal (Lechpammer et al, 2008), prostate (Landers et al, 2008), breast (Kominsky et al, 2003), cholangiocarcinoma (Bunthot et al, 2012) and pancreatic cancer.…”