Frequent silencing of popeye domain-containing genes, BVES and POPDC3 , is associated with promoter hypermethylation in gastric cancer

Abstract

The Popeye domain-containing (POPDC) genes BVES, POPDC2 and POPDC3 encode proteins that regulate cell-cell adhesion and cell migration during development. Herein, we report the frequent downregulation of BVES and POPDC3 by promoter hypermethylation in gastric cancer. POPDC expression in 11 gastric cancer cell lines and 96 paired gastric tumor and normal adjacent tissues was analyzed with quantitative reverse transcription-polymerase chain reaction. The methylation status of BVES and POPDC3 was analyzed with methylated DNA immunoprecipitation sequencing, bisulfite sequencing and pyrosequencing. Expression of BVES and POPDC3 was downregulated in 73% of the gastric cancer cell lines and in 69% (BVES) and 87% (POPDC3) of the gastric cancer tissues. The BVES and POPDC3 promoter regions were hypermethylated in the gastric cancer cell lines in which they were silenced. Combined treatment with a DNA methylation inhibitor and a histone deacetylase inhibitor strongly induced BVES and POPDC3 expression. BVES and POPDC3 were hypermethylated in 69% (BVES) and 64% (POPDC3) of the gastric cancer tissues. We knocked down POPDC3 expression with short hairpin RNAs and examined the consequences on cell migration and invasion. Knockdown of POPDC3 in SNU-216 cells caused increased cell migration and invasion. Thus, epigenetic inactivation of BVES and POPDC3 occurs frequently in gastric tumors and may promote gastric cancer cell migration and invasion.

Epigenetic regulation ofmicroRNA-10band targeting of oncogenicMAPRE1in gastric cancer

“…We identified the aberrant methylation of several genes and suggested roles for these genes in gastric carcinogenesis. [23][24][25][26][27] In this study, we applied methylation array technology to detect the aberrant methylation of miRNA genes in gastric cancers and found heavy methylation on promoter CpGs of miR10b, which is a regulator of multiple aspects of cancer biology the methylation status of two miR-10b promoter regions in gastric cancer cells with bisulfate pyrosequencing analysis of six CpG sites (two in Region 1 and four in Region 2; Fig. 1C).…”

BVES regulates EMT in human corneal and colon cancer cells and is silenced via promoter methylation in human colorectal carcinoma

“…Both claudin-3 and -7 are hypermethylated in esophageal squamous cell carcinoma (29), with the absence of claudin-7 associated with loss of E-cadherin and increased invasiveness (30). Claudin-6 (31), -7 (32), and occludin (33) are hypermethylated in breast cancer, and Feng et al, using a candidate gene approach and MethyLight assays, found that BVES was hypermethylated in non-small cell lung cancer (34); both POPDC3 and BVES were hypermethylated and underexpressed in gastric carcinoma (35). Presumably, these epigenetic events translate into skewing toward a mesenchymal phenotype ultimately realizing a survival advantage.…”

BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis

“…Blood vessel epicardial substance ( BVES/POPDC1 ) is a tight junction-associated protein often silenced in carcinomas secondary to promoter hypermethylation 11–13 . Restoring BVES expression in CRC cell lines promotes epithelial-like morphology and decreases proliferation, migration, invasion, xenograft tumor growth, and metastasis, together indicating broad regulatory capabilities 11 .…”