SOSTDC1 down-regulation of expression involves CpG methylation and is a potential prognostic marker in gastric cancer.

Abstract

Sclerostin domain containing 1 (SOSTDC1) is reportedly down-regulated in various cancers. Our purpose was to study whether epigenetic mechanisms were involved in the down-regulation of expression in gastric cancer. Expression analysis of SOSTDC1 in gastric cancer cell lines indicated mRNA down-regulation. Our reporter assays and gene reactivation studies using 5-aza-2'-deoxycytidine, a DNA demethylating agent, and trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, demonstrated that epigenetic mechanisms are involved in the down-regulation of SOSTC1 expression. Methylation analysis of the SOSTDC1 promoter CpGs using methylation-specific polymerase chain reaction analysis revealed methylation in gastric cancer cell lines and tissue samples. A majority of tumors (17 of 18) with observed methylation exhibited down-regulation of mRNA expression relative to apparently normal gastric tissues. Immunoreactivity for SOSTDC1 in gastric tumors (24 of 46, 52.1%) was down-regulated relative to normal tissues (36 of 38, 94.7%) (P = 0.00001). The difference in expression between gastric tumor subtypes, intestinal and diffuse, was significant (P = 0.040). Expression of SOSTDC1 in gastric tumors increased the probability of both overall and disease-free survival. When overexpressed in AGS cells, cell proliferation, cell cycle progression, and anchorage-independent growth was repressed. The present findings indicate SOSTDC1 down-regulation involves methylation; SOSTDC1 expression is a potential prognostic factor and tumor suppressor in gastric cancer.